XIX International Congress of Neuropathology

MM1: Mentors’ Message to Young Neuropathologists 1. “Neurodegeneration”

History of clarifying pathogenesis of neurodegenerative disease and development of neuropathology

Yoshio Hashizume

Institute of Neuropathology, Fukushimura Hospital, Aichi, Japan

In this lecture, I would like to talk about the role of neuropathology in nearly 50 years of effort in clarifying pathogenesis of neurodegenerative disease. After graduating from medical school in 1969, I majored in neurology and had been engaged in research and education of neuropathology thereafter. I would like to talk about 4 diseases in particular, i.e., spinocerebellar degeneration, Lewy body disease, progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS), in regard to the changes within the history of disease concepts, neuropathological features, and the history of clarifying pathogenesis.

As for spinocerebellar degeneration, I'd like to address the themes ranging from the historical descriptions of sporadic olivo‐ponto‐cerebellar atrophy, striatonigral degeneration, and Shy‐Drager syndrome to disease concept proposal of multiple system atrophy, and discovery of glial cytoplasmic inclusion and of α‐synuclein as a causal protein. Also, for hereditary case, I'd like to review disease classification by identifying causal genes, understanding of triplet repeat disease, and the significance of intranuclear inclusion.

As for Lewy body disease, I'd like to review the history of Parkinson's disease, which began from the description of Lewy body, establishment of concept of dementia of Lewy body disease as dementia, α‐synuclein deposition, development of intracerebral lesions, and pathological changes of whole body organ.

As for PSP, I'd like to talk about the history of PSP and corticobasal degeneration, neuropathological characteristics, development of neuropathological staining technology, establishment of roles of glial cell, and 4R tauopathy.

For ALS, I'd like to talk about the characteristics of classic ALS, ALS with dementia (ALS‐D), frontotemporal degeneration with ubiquitin positive inclusion (FTLD‐U), TDP‐43 discovery, importance of frozen brain and brain bank, a new classification of frontotemporal degeneration (FTLD).

Lastly, I would like to emphasize the importance of neuropathology to young generations who are studying neuropathology. Looking back at the historical transition of neurodegenerative diseases, understanding of neuropathology is essential for the establishment of disease concept, interpretations of images such as magnetic resonance imaging (MRI), association with clinical neurological symptomatology, and clarification of molecular biological genetic research.

MM2: Mentors’ Message to Young Neuropathologists 2. “Developmental Neuropathology”

Developmental Neuropathology

Kinuko Suzuki^1,2

¹Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill; ²Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology

In the process of normal brain development, cascade of molecular as well as structural alterations take place. The formation of the brain is very complicated process. It is quite astonishing to learn how precisely normal developmental process proceed. Any deviation from the normal development results in a formation of “abnormal brain”. The resulting brain contains basic components of the normal brain but assembled in an abnormal way. Depending on the extent of deviation, the brain may show uniquely specific pathological outcome, regardless of the specific etiologic factors. Etiologic factors that initiate molecular and structural abnormalities are variable and the timing of the insult on the developing brain is important determining factor on the outcome of the pathological phenotype. In my lecture, I would like to review the basics of neuropathology in the pediatric age‐group.

For the matter of convenience, I will select 4 major stages (periods) of brain development and discuss the pathological changes. The 1st stage is the stage of neurulation (neural tube formation), The 2nd is the stage of ventral induction (prosencephalon formation and midline patterning). The 3rd stage is the period of the brain growth, cellular proliferation and migration. The 4th stage is the 2nd half of fetal life to postnatal years and period of cerebral cortical organization. Deviation from the normal developmental pattern during the 1st, 2nd and 3rd period results in the uniquely and grossly abnormal brain but pathologic changes during the 4th period may be very subtle on routine morphological examination of the brain.

Reference

Friede, R.L: Developmental Neuropathology (Springer‐Verlag)

Adle‐Biassette H, Harding, B.N, Golden, J.A.: Developmental Neuropathology, 2nd edition (Willey Blackwell)

Suzuki, K. Neuropathology of Developmental abnormalities. (Review Article) Brain and Development 29 (2007) 129‐141.

SP: Special Seminar

Antisense therapy for Fukuyama congenital muscular dystrophy (FCMD) and recent advance in dystroglycanopathies, FCMD, ISPD, and LGMD2I

Tatsushi Toda

Department of Neurology, Graduate School of Medicine, The University of Tokyo

Fukuyama muscular dystrophy (FCMD) and muscle‐eye‐brain (MEB) disease are similar disorders characterized by congenital muscular dystrophy, brain and eye anomalies. Hypoglycosylation of α‐dystroglycan (α‐DG) are common characteristics of these dystroglycanopathies. We identified the genes for FCMD (fukutin) and MEB (POMGnT1). FCMD is the first human disease found to result from ancestral insertion of a SVA retrotransposon. We show that aberrant mRNA splicing, induced by SVA exon‐trapping, underlies the molecular pathogenesis of FCMD. Introduction of antisense oligonucleotides (AONs) targeting the splice acceptor, the predicted exonic splicing enhancer and the intronic splicing enhancer prevented pathogenic exon‐trapping by SVA in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O‐glycosylation of α‐DG and laminin binding by α‐DG. Thus, we have demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD.

Recently we identified the previously unknown glycan unit ribitol 5‐phosphate (Rbo5P), a phosphoric ester of pentose alcohol, as a tandem repeat that functions as a scaffold for the formation of the ligand‐binding moiety of α‐DG. We determined the enzyme activities of three major α‐DGpathy‐causing proteins to be involved in the synthesis of tandem Rbo5P. ISPD is cytidine diphosphate ribitol (CDP‐Rbo) synthase. Fukutin and fukutin‐related protein are Rbo5P transferases that use CDP‐Rbo. Consequently, Rbo5P glycosylation is defective in α‐DGpathy models. Supplementation of CDP‐Rbo to ISPD‐deficient cells restored α‐DG glycosylation. These findings expand our knowledge on post‐translational modification, and reveal the pathogenesis and therapeutic strategies of α‐DG‐associated diseases.

MM3: Mentors’ Message to Young Neuropathologists 3. “Muscle Pathology”

What I have learnt from muscle research

Ikuya Nonaka

National Center of Neurology and Psychiatry

1) Back ground: When I graduated Kumamoto University Medical School around 50 years ago, most of patients with muscular dystrophies had stayed in home with no education and no medical care. There was very heavy discrimination against muscular dystrophies. Then our Government started to establish special muscle disease units in 27 National Sanatoria Hospitals where small children had education and rehabilitation. I worked in one of the hospital and tried to establish a small diagnostic laboratory.

2) Muscle histochemistry: A. Fixation for frozen sample

Dip the sample quickly in isopentane cooled by liquid nitrogen or in mixed solution of dry ice and acetone; SHAKE the tissue in solution for 1 min.

B. ATPase staining

Try pre‐incubation solution at various pHs (pH 10.5, 10.6, 10.7, 10.8 10.9 and 11.0), (pH 4.7, 4.6, 4,5, 4.4, 4,3 and 4.2) and select the best differentiated one

C. PAS (periodic acid Schiff) staining for glycogen

Since glycogen particles are washed out during staining for frozen section, please use epoxy resin 1μm section in Schiff solution for 1 hour.

3) Electron microcopy (EM): An important way to know pathogenetic mechanism (!) ,

Electro‐cytochemistry (cytochrome C oxidase: COX EM) is also available

4) Muscle imaging: Muscle CT/MRI is useful to know disease distribution and to select the best muscle for biopsy. There are many disease specific neuro‐imaging features.

5) Muscle tissue repository: For future research works and gene counseling all muscle biopsies must be kept

In deep freezers at ‐80 degrees in centigrade.

MM4: Mentors’ Message to Young Neuropathologists 4. “Brain Tumor Pathology”

History of brain tumor classification

Yoichi Nakazato

Department of Pathology, Hidaka Hospital

Tumors developed in the cranial cavity are called brain tumors. Their cells of origin are multiple, including neuroepithelial cells, meningothelial cells, nerve sheath cells, mesenchymal cells and so on. Accordingly, there are many tumor types and subtypes: for example, more than 160 tumors are listed in the current WHO classification. It is, therefore, essential to classify correctly these tumors for the management of patients as well as for basic investigation. More than a century ago, brain tumors were classified according to their macroscopic and microscopic features. These schemes are called “morphological classification”. In the early 20th century, neuropathologists became to classify tumors based on their cells of origin and cellular developmental stage. This kind of scheme is called “histogenetic classification”. The representative one is a classification published by Bailey and Cushing in 1926. In the mid‐20th century, the concept of grading was introduced in the brain tumor classification. Grading of tumor became popular among clinicians and general pathologists. Meanwhile, the international classifications, particularly those planned and published by WHO, are now a standard of brain tumor classification, and have been used worldwide. The first edition of WHO's was published in 1979, and several revisions have been made until now. The latest edition is characterized by the inclusion of genetic abnormalities in the nomenclature of tumors. Advancement of pathologic methods was another important driving force for the development of classification. Lastly, the future perspectives of brain tumor classification will be presented.

Diagnostic Slide Session: DSS‐1

A left parietooccipital lesion of 73‐year‐old male with right hemianopsia and sensory aphasia

Manabu Hattori¹; Akio Akagi²; Mari Yoshida²

¹Department of Neurology, Daido Hospital, Nagoya, Japan; ²Institute for Medical Science of Aging, Aichi Medical University

Clinical History: A 73‐year‐old right‐handed male, who had been prescribed donepezil hydrochloride for treating dementia for the past four years, presented because of difficulty in seeing the right visual field.

Consciousness was clear, and there was no problem in verbal understanding and speech. Visual field test showed right hemianopsia. There was no paralysis of the limbs, but walking was unstable. All tendon reflexes disappeared. Orthostatic hypotension was present.

Magnetic resonance imaging (MRI) at the time of admission showed a small high‐signal lesion in the diffusion‐weighted image in the left occipital lobe, and antiplatelet drug was started as cerebral infarction.

Although sensory aphasia appeared on the fourth day of hospitalization, no corresponding infarct lesions were observed in MRI. Cerebrospinal fluid test showed protein elevation (85 mg/dL). Cerebral blood flow SPECT showed increased blood flow in the left temporal lobe, parietal lobe, and occipital lobe. MRI on the 18th day showed gadolinium enhancement on cerebral cortex and low‐intensity signal in T2‐weighted image in the cerebral white matter of the matching site.

Brain biopsy was performed from left parietal lobe on the 25th day of hospitalization for diagnosis.

Aphasia improved without treatment, but acute pancreatitis occurred on day 64. He died, and an autopsy was conducted.

Presented samples: Hematoxylin‐eosin staining of the left parietooccipital lobe lesion.

DSS‐2

An 85‐year‐old female with advanced dementia progressing over the course of 5 years

Kanako Komatsu¹; Saori Onuma²; Tadashi Tsukamoto³; Kazuko Hasegawa²; Hidehiro Mizusawa³; Shigeo Murayama⁴; Yuko Saito¹

¹Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology ang Psychiatry; ²Department of Neurology, National Hospital Organization Sagamihara National Hospital; ³Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry; ⁴Brain Bank for Aging Research, Department of Neuropathology, Department of Neurology Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Case: 85‐year‐old female

Chief complaint: Memory loss

Present illness: At 81 years of age, the patient presented with mild forgetfulness and numbness in the lower right side of the body. She had difficulty with language comprehension and expression. Her scores on the Mini Mental State Examination (MMSE) and the Frontal Assessment Battery (FAB) were 23/30 and 6/18, respectively. Diffusion‐weighted magnetic resonance imaging (DW‐MRI) revealed high intensity areas on both sides of the cerebral cortex.

Two months later, the numbness had spread to the right upper limb, and 6 months later, she started to wander around occasionally. By 82 years of age, the high intensity area identified on DWI had gradually expanded, and progression of cerebral atrophy was also observed. The same year, she experienced a left femoral head fracture and began to use a wheelchair. At 83 years of age, she was hospitalized. The conversation was not possible, and the MMSE could not be administered due to the progression of cognitive dysfunction. There were rare spontaneous movement. Episodic laughter stood out. The patient required the help of a caregiver at all times. Although spontaneous movement or speech were rare, but meal intake was orally possible with assistance. CSF examination showed that Tau protein was negative (460 pg/ml). Electroencephalography showed diffuse θ waves. At 84 years of age, limb myoclonus and startle reflex were observed, and the patient remained asleep. She continued meal intake, but often choked on her food.

She died at 85 years of age. Autopsy was performed 23 hours and 56 minutes after death.

Necropsy findings: The weight of the brain was 1186 g.

Virtual slides: Hematoxylin–eosin and immunohistochemically stained section of hippocampus

MRI (84 years of age): DWI

DSS‐3

An autopsy case of 62‐year‐old male with FTLD – MND and parkinsonism

Hidetomo Tanaka; Ryoko Koike; Hitoshi Takahashi

Department of Pathology, Brain Research Institute, Niigata University

Clinical History: A 58‐year‐old Japanese man developed stiffness in the right leg and this symptom progressed gradually. He also developed tremor in the bilateral arms and right leg. After 4 months, he visited a hospital. On examination, he showed spasticity in the right arm, and mild muscle weakness, with positive Babinski sign, in the right leg. Increased deep tendon reflexes were also present in the upper and lower extremities. About 6 months after onset, he showed mild muscle weakness in the bilateral upper and lower extremities. Electromyography (EMG) showed neurogenic changes in the tongue, sternocleidomastoid, femoral rectus, and anterior tibial muscles. Brain and spinal cord MRI revealed no apparent abnormalities. A tentative clinical diagnosis of motor neuron disease (MND) was made.

At the age of 60, he became unable to walk. At the age of 61, dysphagia appeared and progressed, necessitating the introduction of tube feeding. He developed dementia with a HDS‐R* score of 13 (*the revised version of the Hasegawa dementia scale; a mental examination method commonly used in Japan that utilizes a scale of 0 to 30, where <21 represents dementia). Atrophy and fasciculation were evident in the tongue, and rigospasticity was present in the neck, with retrocollis. Vertical (both upper and lower) eye movement was mildly limited. He was treated with L‐dopa without noticeable effect. At this point, an alternative clinical diagnosis of progressive supranuclear palsy (PSP) was considered. At the age of 62, he exhibited severe dementia with a HDS‐R score of 4, and brain MRI revealed frontotemporal cerebral atrophy. The patient died of pneumonia, about 4 years after onset of the disease. There was no family history of neurological diseases.

Autopsy findings: The brain weight was 1,090 g (fresh). There was atrophy of the frontotemporal lobes, which were more accentuated in the precentral gyrus

Material submitted:

Two H&E slides of motor cortex and spinal cord

Points for discussion:

1. Differential diagnosis;

2. Useful immunohistochemical stains

DSS‐4

A 67‐year‐old woman presented with progressive asymmetric weakness and numbness in all four extremities

Ryota Sato; Takashi Kanda

Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine

Present illness;: 　A 67‐year‐old woman presented with a three‐month history of progressive asymmetric weakness and numbness in her limbs.

Blood exam: 　WBC 21840 /μl, RBC 352x10⁴ /μl, Hb 12.0 g/dl, Ht 34.9 %, PLT 10.3x⁴/μl

CRP 3.26 mg/dl, ESR1h 108 mm, HbA1c 5.7%, sIL‐2R 906 U/ml

ANA (+), anti ds‐DNA antibody (‐), anti RNP antibody (+), anti SS‐A antibody (+)

anti SS‐B antibody (‐), PR3‐ANCA (‐), MPO‐ANCA (‐)

Cerebrospinal fluid: normal

Nerve conduction study: asymmetric demyelinating sensory‐motor polyneuropathy.

Radiological findings: Para‐aortic nodes were enlarged, but any tumors didn't be found in contrast enhanced CT. There were no enlarged nerve roots or abnormal signal of brain and spinal cord in contrast enhanced MRI.

Points of discussion: 1. Diagnosis

2. Mechanism of neuropathy

DSS‐5

A right temporal lobe lesion of 18‐year‐old male with intractable epilepsy

Shoko Sadashima; Satoshi O. Suzuki; Toru Iwaki

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University

Case: 18 year old, male

Chief complaint: Complex partial seizure

Past medical history: None

Family history: No history of epilepsy

Present illness: The case is an 18‐year‐old male with normal growth and development without history of febrile convulsion. At the age of 15, the patient developed a symptom of staring and behavioral arrest followed by thrashing the limbs. Electroencephalogram showed epileptogenic waves in the right frontotemporal region, and MRI revealed a lesion in the right temporal lobe. Since the epilepsy was drug‐resistant, right lateral temporal lobectomy and amygdalohippocampectomy were performed.

Physical examinations: Height 169.0cm, Weight 99.0kg, BMI 34.7

BP 129/93mmHg, PR 78/min, RR 16/min, SpO2 98%, room air

Neurological examinations: Consciousness, clear No neurological deficits

(Neuropsychological test: WAIS‐III VIQ 58, PIQ 62, FIQ 57)

MRI: FLAIR (axial, coronal)

Presented samples: Hematoxylin‐eosin staining of the right temporal lobe lesion.

DSS‐6

A 64‐year ‐old man with a 17‐year history of weakness in proximal limbs

Akira Arakawa¹; Masato Kadoya²; Atsushi Unuma¹; Naohiro Uchio¹; Akatsuki Kubota¹; Jun Shimizu¹; Tatsushi Toda¹

¹Department of Neurology, Graduate School of Medicine, The University of Tokyo; ²Division of Neurology, Department of Internal Medicine, National Defense Medical College

Case: 64‐year‐old man

Chief complaint: weakness in proximal limbs

Past medical history: Taking simvastatin 5mg from 57 year old for dyslipidemia

Family history: No history of collagen disease

Present illness: This patient had no muscle symptoms until he was found to have asymptomatic elevated serum CK (5000IU/L) at his age of 47. He was diagnosed as having polymyositis after the examinations including muscle biopsy. He was treated with oral prednisolone (5mg) for 10 years without subjective muscle symptoms, but with elevation of serum CK levels. At his age of 57, he gradually showed arthralgia and weakness in proximal muscles. His serum CK was 5651 IU/L. His second muscle biopsy showed mild myopathic changes with a small amount of inflammatory collections. He was treated with three courses of high dose intravenous methylprednisolone therapy followed by oral prednisolone (52mg), which were effective. At his ages of 59 and 60, he showed exacerbation of weakness associated with serum CK elevation, which was partially responded to immunosuppressive treatment. At his ages of 64, he showed gradual worsening of proximal muscle power with elevation of serum CK again (417 IU/L). He was hospitalized for re‐examination of his muscle disease. He had symmetrical weakness in proximal limbs (4/5). He had no skin rash.

Muscle CT of proximal lower limbs (axial)

Presented samples: Hematoxylin‐eosin staining of left deltoid muscle at his age of 64.

Plenary 1: PL1

Deciphering Tau Neuropathology: From Silver Stain Toward a Near‐atomic Resolution.

Bernardino Ghetti

Indiana University Purdue University Indianapolis, Indiana University School of Medicine, Department of Pathology and Laboratory Medicine

During the decades that followed Alois Alzheimer's 1906 and 1911 discoveries of argentophilic inclusions, now known as neurofibrillary tangles (NFT) and Pick bodies (PiB), many neurodegenerative diseases, characterized by similar inclusions, have emerged. Using the Bielschowsky method or other silver stains, it has been possible to study the neuroanatomical distribution of these inclusions, in sporadic and hereditary syndromes. Since the 1950s, the advent of electron microscopy (EM) has allowed to define a variety of pathologic fibrillary aggregates in neurons and glia. However, it has been the discovery of tau, in 1975, that has marked the beginning of a new era, during which significant progress in understanding neurodegeneration has occurred, along with the discovery of previously unrecognized diseases characterized by tau pathology. Since 1976, the Neuropathology Laboratory, at Indiana University (IU), has been at the forefront in deciphering diseases with neurofibrillary degeneration and tau pathology, not only through the study of forms of dominantly inherited AD, associated to novel APP, PSEN1, and PSEN2 mutations, but also through the discovery of tau pathology in Gerstmann‐Sträussler‐Scheinker disease and Prion Protein Cerebral Amyloid Angiopathy, two dominantly inherited prion protein amyloidoses. The role of tau pathology in neurodegeneration acquired a central position in 1998, when the discovery of mutations in the MAPT gene was key into revealing the phenotypic complexity of the cellular and molecular pathology in tauopathies. In these disorders, intracytoplasmic neuronal and glial tau inclusions derive from the aggregation of six tau isoforms or from the aggregation of isoforms with three or four repeats, resulting in diverse clinical and neuropathologic phenotypes. More recently, studies of NFT and PiB, using Cryo‐EM, revealed, for the first time, the atomic structure of the tau filaments that form these inclusions. The molecular neuropathology of tau in the diseases discovered at IU will be presented in detail.

Plenary 2 (BNS Sponsored): PL2

Structures of tau filaments from Alzheimer's and Pick's disease brains

Michel Goedert

MRC Laboratory of Molecular Biology

The ordered assembly of tau protein into abnormal filamentous inclusions underlies a large number of human neurodegenerative diseases. Tau filaments with distinct morphologies and isoform compositions characterise many of these diseases. Together with experimental studies, this has led to the suggestion that multiple molecular conformers of aggregated tau may exist. Electron cryo‐microscopy can be used to determine the high‐resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer's disease are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304‐E380 (in the numbering of the 441 amino acid isoform of human tau), which adopt a combined cross‐β/ β‐helix structure. They comprise the end of the first or second repeat (R1 or R2), the whole of R3 and R4, as well as 12 amino acids after R4. By contrast, the ordered core of the narrow tau filaments of Pick's disease consists of a single protofilament extending from K254‐F378 of three‐repeat tau, which adopt a cross‐ β structure. It comprises the distal 21 amino acids of R1, all of R3 and R4, as well as 10 amino acids after R4. The wide tau filaments of Pick's disease, which are in the minority, consist of two protofilaments linked by the anti‐parallel stacking of C322‐S324. These findings show that filamentous tau protein can adopt distinct folds in different human neurodegenerative diseases, establishing the existence of multiple molecular conformers of aggregated tau.

PL3

Future of the Japanese Society of Neuropathology

Shigeo Murayama

President, the Japanese Society of Neuropathology

The Japanese Society of Neuropathology (JSNP) has been focusing on neurodegenerative disorders and is quite unique in the world. This may be quite helpful to establish brain bank network in Japan. We now succeed in building up high‐ quality brain bank consortium of neurodegenerative disorders. My first mission is to establish all Japan brain bank network to recruit brain donors of intractable neurological disorders.

The next step is to help consolidate brain banks of psychiatric disorders and, next, establish brain banks of pediatric and developmental neurological disorders.

We are starting the program of JSNP endorsed Board of Neuropathology after this meeting and one of the aim is to educate brain bank neuropathologists

There are several unsolved problems.

1. How to cope with paradigm shift of brain tumor diagnosis.

2. How to collaborate with neuroscientists, especially in genomic research.

3. How to collaborate with forensic pathology.

4. How to collaborate with veterinary pathology.

We form ICN 2018 programs to answer these questions. Any comments are quite welcome.

Symposium 1: S1‐1

Changing concept of microglia: microgliopathies

Atsushi Sasaki

Department of Pathology, Saitama Medical University

Our understanding of microglia function and potential has greatly expanded in recent years. This symposium is aimed to inform about the changing concept of microglia: Microglia influence synaptic density and connectivity; Gut‐microbiota and microglia interact; Some leukodystrophies are considered microgliopathies; Senescent (sick) microglia may contribute to neurodegeneration; Microglial activation and true inflammation need to be distinguished, and neuroinflammation has no precise meaning. Nowadays, mounting evidence indicates that microglia are not in a resting state under healthy conditions, but instead play an essential role in maintaining homeostasis under physiological conditions. The term, microgliopathy, has been applied to disorders due to defects in microglia‐specific gene products and/or in which microglia dysfunction could be at the center of the diseases process. These include roles for DAP12 or TREM2 in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu‐Hakola disease; NHD) and CSF1R in hereditary diffuse leukoencephalopathy with spheroids (HDLS). Interestingly, both DAP12 and TREM2 are implicated in the CSF‐1R signaling cascade, and NHD shows the similar histological findings to those of the cerebral white matter in HDLS. Previous reports indicated that most NHD patients with DAP12 gene mutation had a decreased expression of DAP12 at mRNA and protein levels. The mechanisms by which DAP12/TREM2 or CSF1R dysfunction leads to impairment of white matter maintenance are still largely obscure. Future studies on the microglia‐specific functions of the DAP12/TREM2/CSF1R signaling pathway in healthy and diseased brains are crucial for understanding the detailed pathogenesis of microgliopathies.

S1‐2

Physiological Implications of microglia‐synapse interactions

Hiroaki Wake

Division of System Neuroscience, Kobe University Graduate School of Medicine

Microglia are the sole immune responding cells in the central nervous system. Their role as neuro‐immune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. Upon brain disease and infection, the adopt an activated phenotype associated with the release of cytokines and neurotrophic factors and resulting in neuroprotective or neurotoxic outcomes. However, microglia are resident also in the healthy or physiological brain, but much less is known about their role(s) in the healthy brain, partly due to technical limitations involved with investigate these highly reactive cells in the intact brain. Recent developments in molecular probes and optical imaging in vivo has now helped to characterize microglia in the physiological or healthy brain. In vivo two‐photon imaging of fluorescently labelled microglia have revealed they are highly motile cell in the healthy brain, extending and retracting their process that extend from a largely stationary cell soma. In this issue, we briefly summarize some of the physiological functions of microglia in the uninjured brain, with a focus on interactions they make with synapses.

S1‐3

Single‐cell profiling of the myeloid cell compartment identifies new cell populations with distinct fates during neuroinflammation

Marco Prinz

Institute of Neuropathology, University of Freiburg

The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS) including parenchymal and non‐parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease‐specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. By combining deep single‐cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic lines we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self‐renewal, and random proliferation shifted towards clonal expansion. Finally, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain's innate immune system.

S1‐4

Microglia and neuronal degeneration in senescence‐accelerated mice

Atsuyoshi Shimada

Kyorin University Faculty of Health Sciences

I here present our data on age‐related changes in the morphology of microglia in Senescence‐accelerated mouse prone 10 (SAMP10). In SAMP10 neuronal degeneration begins to appear earlier (around 8 months of age) and becomes progressively more remarkable with advancing age, compared to Senescence‐accelerated mouse resistant 1 (SAMR1) as usual‐aging controls. Parameters representing morphological features and pathological changes of microglia were quantified using an image analyzer. Microglia of SAMP10 mice at ages 3 and 8 months exhibit shortened combined projection length and smaller numbers of segments and tips than those in age‐matched SAMR1 mice. Microglia of SAMP10 mice at all ages are characterized by having frequent pathological changes in processes. These morphological abnormalities in microglia of SAMP10 mice precede the onset of neuronal degeneration and may lead to making brain tissue less protective to neurons. I also present our data on hippocampal tissue responses to intraperitoneal injection of kainic acid (KA) in mice at age 3 months. On day 3 following KA challenge, microglia‐derived interferon‐gamma stimulate astrocytes via the receptors to induce the expression of CXCL10 and CCL3 in SAMR1 mice. Activated microglia produce GM‐CSF and osteopontin. CD44, an osteopontin receptor, is strongly upregulated in neurons. This well‐orchestrated glial reaction is strikingly reduced in SAMP10 mice. Thirty days after KA challenge, SAMP10 but not SAMR1 mice exhibit hippocampal atrophy. Since the osteopontin‐CD44 system is essential for neuroprotection, these findings highlight the defects of SAMP10 mice in cytokine‐mediated neuroprotective glial responses, which may be associated with early microglial abnormalities in SAMP10 mice.

S1‐5

Neuroinflammation and the control of microglia behavior

Manuel B. Graeber

University of Sydney Brain and Mind Centre, Camperdown, New South Wales, Australia

Microglia were first described by Nissl in 1899 as rod cells in cerebral cortex where they are thought to engage in the activity that forms the focus of this Symposium: microglia‐synapse interactions. Robertson also gave an account on microglia in 1900, and del Rio‐Hortega finally named the cells in 1920. However, microglia were initially ignored by neuroimmunologists in the 1980s when astrocytes were incorrectly considered the main antigen presenting cells of the CNS. Over the last two decades microglial cells have been trivialized as macrophages although their presence in normal adult brain and spinal cord tissue is quite obviously not associated with macrophage activity. In addition, the question what exactly microglia do in classical non‐inflammatory brain pathologies that light up on PET imaging has remained an open question. The tautological term “neuroinflammation” effectively denotes gliosis. We think it is likely that synaptic changes involving both astrocytes and microglia are the reality behind most claims of “brain inflammation” in classical non‐inflammatory conditions such as autism, schizophrenia, depression, obesity and several forms of dementia to name a few. This lecture will focus on the engraftment of genetically modified bone marrow‐derived microglia precursors, which we first reported in 1998 (Journal of Neuroimmunology 90:27/136). In our axotomy experiments, blood‐derived cells assumed the typical morphology and even position of perineuronal activated microglia. Therefore, non‐invasive access to the CNS via bone‐marrow derived genetically modified microglia precursors should be a strong focus of research. We will discuss means to control these neo‐microglia that may affect synapses.

Symposium 2: S2‐1

Calcium channel protein aggregations and role of lysozomes in SCA6

Kinya Ishikawa

The Center for Personalized Medicine for Healthy Aging, Tokyo Medical and Dental University

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by a polyglutamine (polyQ) expansion [control: 4 ˜ 20Q; SCA6: 20 ˜ 33Q] in the carboxyl(C)‐terminal cytoplasmic domain of the α1A voltage‐dependent calcium channel (Cav2.1). The length of polyQ tract in SCA6 is the shortest among the nine polyQ diseases. Although the pathogenesis of SCA6 remains elusive, several fundamental observations suggest two plausible hypothesis. One is that a small polyQ expansion in a large membranous Cav2.1 protein leads to aggregation within the cytoplasm of SCA6 Purkinje cells. The other is that a shorter carboxyl‐terminus of the Cav2.1 containing polyQ tract preferentially translocates into Purkinje cell nuclei, where it affects transcription of several genes involved in neurite outgrowth such as TAF1. On western blot, Cav2.1 C‐terminal fragment is detected in the nuclear fraction from human SCA6 cerebella. Importantly, Cav2.1 protein aggregation is far more abundant in the cytoplasm compared to nucleus. This is convincingly recapitulated in SCA6 knock‐in mice expressing Cav2.1 with 118 polyQ. We found that antibodies against the lysosomal proteases cathepsin B (CaB) or cathepsin D (CaD) are both strongly immunoreactive in human SCA6 Purkinje cells. In accord with this, CaB‐ and CaD‐immunoreactivities are intense in SCA6 knock‐in mice. Furthermore, lack of CaB exacerbated Purkinje cell loss with acceleration of Cav2.1 aggregation, suggesting that lysosomal enzyme(s) protect against polyQ‐induced toxicity. Further studies investigating whether activating lysosomal catalytic enzymes is essential for mitigating polyQ‐induced toxicity.

S2‐2

Autophagic function and dysfunction in Niemann‐Pick type C neuropathology

Andrew Lieberman

Department of Pathology, University of Michigan

Niemann‐Pick type C disease is a fatal, progressive neurodegenerative disorder caused by loss‐of‐function mutations in NPC1, a multipass transmembrane glycoprotein essential for intracellular lipid trafficking. This autosomal recessive lysosomal storage disorder is characterized by progressive neurodegeneration and early death, often in childhood. I will review data from cell culture and genetic mouse models defining impaired autophagic flux in models of disease. These findings will be extended to the brain of Npc1 deficient mice, where age‐dependent Purkinje cell degeneration is a characteristic feature. Our analysis has demonstrated striking accumulation of autophagic substrates in the diseased brain, including both brainstem and cerebellum. Moreover, our studies establish that ER‐targeted autophagy plays an essential role in degrading I1061T NPC1, the most common disease‐causing missense mutant. Finally, I will discuss on‐going work to develop novel strategies to alleviate neuronal lipid storage for therapeutic benefit.

S2‐3

The effect of impairment of autophagy versus lysosomal proteostasis on the survival of Purkinje cells

Masato Koike

Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan

Neurological phenotypes of cathepsin D (CD)‐deficient mice, a murine model of neuronal ceroid lipofuscinoses (NCLs), indicate the importance of CD in the lysosomal proteostasis in CNS neurons. Furthermore, it is well known that impairment of autophagy leads to neurodegeneration. Because human patients with mutation in CD or autophagy related genes exhibit ataxia, we generated CD‐deficient mice specifically in Purkinje cells (PCs), whose phenotypes were compared with those of PC‐selective Atg7‐deficient mice.

Oral 1: O1‐1

Cerebral amyloid angiopathy initially occurs in the meningeal vessels

Shigeki Takeda¹; Kazunori Yamazaki²; Teruo Miyakawa²; Kiyoshi Onda²

¹Department of Pathology, Niigata Neurosurgical Hospital; ²Department of Neurosurgery, Niigata Neurosurgical Hospital

To clarify the regional frequency of cerebral amyloid angiopathy (CAA), we counted sections of blood vessels showing positive staining for Aβ in the subarachnoid space (SAS) and cerebral cortex (CC) using paraffin‐embedded sections of the frontal, temporal and occipital lobes. The specimens had been taken for routine neuropathological examination from the brains of 105 Japanese patients (aged 40‐95 years) selected from among 200 consecutive patients autopsied at our hospital. We examined the anatomical ratios of blood‐vessel sections in the SAS relative to the CC in 3 selected CAA cases, and those of Aβ‐positive blood‐vessel sections in CAA cases. CAA was found in 53 of the 105 cases. The anatomical ratio of blood‐vessel sections in the SAS relative to the CC was 1/3.70‐1/4.37 (mean: 1/3.94). The ordinary CAA group, in which CAA was seen in both the SAS and CC, included 41 cases (77.4%). In 37 of these cases, the SAS/CC ratio of Aβ‐positive blood vessels was 1/0.05‐1/0.66 (mean: 1/0.26), and in the other 4 cases the ratio was 1/1‐1/1.5. In the ordinary CAA group, the SAS/CC ratio of Aβ‐positive blood vessels was smaller than the anatomical ratio. The meningeal CAA group, in which CAA was found only in the SAS, included 12 cases (22.6%). These patients ranged in age from their fifties to their nineties. There was no case in which CAA was limited only to the CC. We concluded that CAA initially develops in the meningeal blood vessels, and not in the cortical blood vessels.

O1‐2

iatrogenic Embolization Causing Stroke Following Cardiac Intervention

Tyler Hickey¹; Asaf Honig³; Avrum Ostry²; Jason Chew⁵; James Caldwell⁴; Michael Seidman^2,4; Hamid Masoudi²; John Maguire¹

¹Dept. of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver; ²Dept. of Pathology and Laboratory Medicine, St. Paul's Hospital, Vancouver; ³Neurology, University of British Columbia; ⁴Dept. of Radiology, University of British Columbia; ⁵Department of Radiology, Vancouver General Hospital

Introduction: Iatrogenic cerebral embolization following cardiac investigative procedures may result from polymer sheaths of catheters (HPE), cardiac valve calcifications (CVC), and air embolism from open heart surgery. This retrospective clinical pathologic analysis was undertaken to ascertain the frequency and extent of this potentially fatal complication.

Methods: This retrospective clinical pathologic autopsy analysis with pre‐mortem diagnostic imaging correlation identified 110 individuals who had undergone endovascular procedures between 2010‐2016 within 90 days of death followed by hospital autopsy. Clinical outcomes, radiologic studies and autopsy materials were reviewed.

Results: Histologic evidence of HPE was found in 25% (25/102), 54% (26/48) showed evidence of infarction in post‐procedural imaging, with radiologic evidence of infarction in 32% (8/25) of cases with HPE histology. The HPE‐involved organs included: kidneys (n=13), lungs (n=8), heart (n=7), spleen (n=4), brain (n=2), liver (n=2), pancreas (n=2) and colon, stomach, adrenal gland and skeletal muscle. Endovascular aortic repair was associated with the greatest density/distribution of HPE. HPE material showed degradation with time and was often associated with an inflammatory response including multinucleated giant cells. HPE directly contributed to death in three cases. Six cases of calcified cerebral emboli complicated aortic valve procedures. One fatal air embolism followed open heart surgery, and one cardiac tissue embolus resulted in a major stroke.

Conclusions: We advocate for greater awareness of these under‐recognized and occasionally fatal complications of endovascular procedures. Targeted post‐procedural imaging has a role in the identification of iatrogenic embolic infarcts.

O1‐3

Slow compression brain injury: clinical case and animal model

Toshihiko Kuroiwa¹; Jun Oki¹; Hitoshi Tabata¹; Shu Endo²

¹Department of Pathology, Tsuchiura Kyodo General Hospital Namegata District Medical Center; ²Animal Research Center, Tokyo Medical and Dental University

Brain shows atrophy by slow compression. However, little is known about the neuropathological features of compressed tissue. We examined pathological changes of a brain with slow compression by meningioma, and developed an animal model of slow compression brain injury.

Clinical case: An autopsied brain of 75 years old male with frontal meningioma was cut and three large coronal section brain specimens stained with Kluever‐Barrera or Bodian method were made. Thickness of peri‐tumoral gray matter was 0.33±0.22 (m±SD) of the control. Cross sectional area of ipsilateral hemisphere was reduced to 0.77±0.02 of the opposite side. Nuclear height/width ratio of neuron was significantly reduced in the peri‐tumoral brain tissue to 0.48±0.13 from the control. The reduction of height/width ratio was in parallel with the reduction of gray matter thickness.

Animal model: A device for slow compression was installed on the parietal cortex of Japanese white rabbits (n=9) and gradually compressed (100 µm/day) for 56.0±1.3 days. Cortical thickness decreased to 0.19±0.07 of the control, cross sectional area decreased to 0.63±0.10 of the control, Nuclear height / width ratio of the neuron decreased to 0.43±0.10 from the control. Neurite density was decreased in Golgi staining specimens. Coiling of perforating artery was observed in the soft‐X‐ray angiography, but the regional cerebral blood flow measured by the hydrogen clearance method was kept at 0.95±0.17 of the control.

Conclusion: Slow brain compression causes no regional blood flow change, but tissue atrophy, neuronal deformation and reduction of neurite density.

O1‐4

Chronic traumatic encephalopathy: The role of gliovascular pathology

Marc Harris Goldfinger; Bension Tilley; Saniya Mediratta; Magdalena Sastre; Steve Gentleman

Division of Brain Sciences, Imperial College London

Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive mild traumatic brain injury (mTBI). Currently, CTE may only be diagnosed post‐mortem, by examining the deposition of tau in both astrocytes and neurons around the cerebral microvasculature at the depths of sulci. The gliovascular unit (GVU) is known to be disrupted in the acute phase of traumatic brain injuries. Due to the proximity of the tau pathology to the vasculature in CTE, we investigated whether the GVU is also disrupted in individuals with CTE pathology.

Methods: We studied the brains of 10 boxers, from the Corsellis archival collection, who were diagnosed with CTE according to modern diagnostic criteria. Using immunohistochemistry and tissue clearing (FASTClear), we have investigated tau pathology, blood‐brain‐barrier integrity, basement membrane composition and the morphology of the glial limitans.

Results: We observed widespread disruption of multiple GVU components, with extravasation of blood‐borne fibrinogen, as well as fibrinogen within astrocytes, some of which exhibited tau pathology. Disruption of the glial limitans was a common feature, manifest as retraction of astrocytic end‐feet and a change in the composition of the basement membrane. These disruptions were also evident in areas where tau pathology was not present.

Conclusion: CTE tau pathology is shown to be associated with several aspects of GVU disruption. In addition, the same pathology is seen independently of tau, indicating that GVU pathology may precede tau deposition. This may also indicate that GVU disruption may play a role in the underlying mechanism behind the development of CTE.

O1‐5

The neurodegeneration in old single episode head injury is not caused by Alzheimer pathology.

Safa Al‐Sarraj^1,2; Claire Troakes²; Andrew King¹

¹Department of Clinical Neuropathology, Kings College Hospital; ²Brain Bank, The Institute pf Psychaitry, Psycology and Neurosciences, Kings College London

Introduction: Increasing evidence suggests that traumatic brain injury(TBI)is linked to neurodegeneration later in life with increased incidence of Alzheimer disease (AD).Although chronic traumatic encephalopathy (CTE) is known to be linked with repetitive TBI, the association of single episode TBI with the neuro degeneration is not certain. We have recently shown that WNT pathway proteins (DKK1 and beta Catenin) are less altered in AD with TBI compared with AD without TBI.

Methods: We aim to investigate the distribution of Tau, beta A4, TDP43, alpha synucline, ApoJ, DKK1, CD68 in brains from 19 patients (18‐75 y) with severe cognitive decline after 1‐22 years of a single episode TBI.

Results: All brains have significant traumatic axonal and vascular damage due head injury. Three patients (75, 74,56 y) showed Tau Braak stage IV, II, and I respectively. Two patients (50 and 41 y) showed localised CTE pathology stage one associated with high AopJ. All brains are negative for DKK1, alpha synuclein, TDP43.

Conclusion: Neurodegeneration in old single episode TBI is caused by traumatic axonal and vascular injuries but it is unlikely due Taupathy (AD or CTE).

O1‐6

Sequential evaluation of pathological changes following spinal cord injury in a canine model

Yuya Nakamoto^1,2; Gentarou Tsujimoto¹; Akito Ikemoto³; Miwa Nakamoto²; Tsuyoshi Ozawa²; Tatsuo Nakamura¹

¹Department of Regeneration Science and Engineering Institute for Frontier Life and Medical Sciences, Kyoto University; ²Kyoto Animal Referral Medical Center; ³Department of Neurology, Kyoto University Graduate School of Medicine

The purpose of this study was to evaluate the histological findings following induced spinal cord injury in dogs < 2 days and < 2 weeks post‐injury. Eight dogs were included, and spinal cord injury was induced using an epidural balloon catheter. Two dogs were sacrificed at each of four time points: immediately after the procedure, day 1 after the procedure, and at 1‐ and 2 weeks after the procedure. Over the 2 weeks, haemorrhage at the primary injury site expanded quickly, then decreased in size, but spongiform change, parenchymal necroses, and gliosis remained. Rostral and caudal to the primary injury site, haemorrhage, haematoma, and similar changes occurred indicating ascending and descending haemorrhage post‐injury, which resolved over time. Changes were seen in both the gray and white matter. This is the first report to clarify the sequential evaluation of pathological changes following spinal cord injury in dogs.

Symposium 3: S3‐1

Radiation Induced Secondary Glioblastomas in patients with medulloblastomas showed alteration of the PDGFRA and TP53 in whole exome sequencing

Ji Hoon Phi^1,2; Sung‐Hye Park³; Seung Ah Choi^1,2; Ae Kyung Park⁵; Ji Yeoun Lee^1,2,4; Kyu‐Chang Wang^1,2; Seung‐Ki Kim^1,2

¹Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea; ²Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; ³Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; ⁴Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea; ⁵College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea

Introduction: Currently, at least 1/4 of all patients with medulloblastoma suffer from tumor recurrence and the prognosis of recurrent MB (rMB) is dismal. Secondary malignancies such as glioblastoma (GBM) are rarely occurred in recurrent tumors after radiotherapy for MB patients.

Methods: We performed whole exome sequencing (WES) in recurrent tumors of MBs and found 5 cases of RT induced secondary GBM (secondary GBM). The authors compared genomic and histopathological findings of secondary GBMs with rMBs.

Results: The man age of initial tumor occurrence was younger in secondary GBMs than rMBs [5.58: 11.16 yrs], however, the mean age of recurrent tumors was similar [13.7: 14.2 yrs] because the time interval between primary and recurrence was longer in secondary GBMs than rMBs (8.1: 3.0 yrs). Three out of 5 cases of secondary GBMs were misdiagnosed as anaplastic variant of rMB. All secondary GBMs were positive for GFAP and Olig2, but not for rMBs. On WES, missense mutations or complex gene fusion in PDGFRA with augmented expression and genomic alterations of TP53, including loss or germline/somatic mutations of 17p, were found in secondary GBMs. On the other hand, rMBs revealed the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already existed in primary MBs.

Conclusion: The recognition of this secondary GBM is critical to finding secondary GBM. The PDGFRA and TP53 might play an important role in the development of a second malignancy and PDGFRA and EZH2 can be potential therapeutic targets in these fatal recurrent tumors.

S3‐2

Astroblastoma is pathologically and genetically distinct from other mimics

Takanori Hirose^1,2; Sumihito Nobusawa³

¹Department of Pathology for Regional Communication, Kobe University Graduate School of Medicine; ²Department of Diagnostic Pathology, Hyogo Cancer Center; ³Department of Human Pathology, Gunma University Graduate School of Medicine

Astroblastoma is a rare, enigmatic tumor, which microscopically mimics ependymoma, and papillary meningioma, although some controversy remains regarding its distinctiveness. Recent molecular analyses of CNS primitive neuroectodermal tumors revealed some unique genetic aberrations in a subset that shared the clinicopathologic characteristics of astroblastoma. Astroblastoma predominantly affects children and young adults and shows a female preponderance. It usually arises in the cerebral hemisphere. Radiological examinations demonstrate a well‐demarcated tumor, which is often associated with enhancement. Microscopic characteristics are well‐developed perivascular pseudorosettes and perivascular hyalinization. The former are formed by the angiocentric arrangement of broad, short cell processes of tumor cells and are known as “astroblastic pseudorosettes”. Astroblastoma is pathologically classified as low‐grade or high‐grade, based on anaplasia and proliferative activity, but diagnostic criteria and formal WHO grades have not been established. Astroblastoma usually shows immunoreactivity for GFAP and Olig2 in varying proportions. A dot‐like reaction for EMA is also seen in some cases. Recently, astroblastoma was reported to possess MN1 gene rearrangement, which may form an aberrant fusion gene with BEND2 located on the X chromosome. Chromothripsis is suspected to be involved in the translocation of the X chromosome. Although high‐grade astroblastoma is generally more aggressive, patients able to undergo total resection may follow an indolent clinical course. Considering the unique clinicopathologic features and distinct molecular profiles, astroblastoma is considered a distinct tumor entity despite several similarities with other glial tumors, especially ependymoma.

S3‐3

CNS Embryonal Tumors beyond the WHO 2016 Classification

Vani Santosh

Department of Neuropathology, National Institute of Mental Health & Neurosciences, (NIMHANS)

CNS embryonal tumors encompass a wide spectrum of histomolecular entities that are incorporated in the WHO 2016 classification. This includes the four new genetic subgroups of medulloblastoma (WNT activated; SHH activated,TP53mutant; SHH activated,TP53wildtype; nonWnt/nonSHH). Embryonal tumour with multilayered rosettes (ETMR) form their own group, sharing the common alterations in the oncogenic C19MC cluster. The diagnosis of Atypical Teratoid/Rhabdoid Tumors (AT/RT) mandatorily requires demonstration of mutation or loss of SMARCB1 or SMARCA4 genes. The CNS PNET entity is now obsolete, and the remaining tumours classified based on histology alone are termed other embryonal tumours. Following the WHO 2016 classification, high throughput data sets have identified newer molecular subgroups within embryonal tumors, such as; 7to12 molecular subgroups in medulloblastoma, each with its own clinical behavior. We have shown that mitochondrial DNA content based clustering identifies five subgroups of medulloblastoma. Three molecular subgroups of AT/RT which are genetically similar but epigenetically different are identified; AT/RT TYR, AT/RT SHH and AT/RT MYC. Newer embryonal tumor molecular entities that are not included in the WHO diagnostic lexicon include; CNS neuroblastoma FOXR2 activation, CNS Ewing sarcoma family tumor EFT&CIC alteration, CNS high grade neuroepithelial tumor with MN1 and BCOR alteration. Tumors that resemble CNS embryonal tumors histologically include pineoblastomas and the newly described pituitary blastoma. Germ line mutation in DICER1 is reported to be a key predisposing event in pituitary blastomas. The clinical significance of these newer molecular subtypes of CNS embryonal tumors would determine their practical incorporation into subsequent CNS tumor classifications.

S3‐4

Are IDH wt diffuse astrocytomas glioblastomas in disguise ?

Ho ‐Keung Ng

Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong

During the making of the WHO2016 classification, there was intense debate whether truly low grade diffuse IDH wt astrocytomas exist. The entity was finally retained reluctantly though it was noted that many of them would be glioblastoma in disguise. The TGCA paper (NEJM 2015) of lower grade gliomas more or less arrived at the same conclusion. We and some others propose that while many of IDHwt diffuse adult astrocytomas will indeed behave like high grade gliomas, a significant proportion will behave more indolently and have survivals worse than IDH mutant astrocytomas but much better than glioblastoma. The high risk and low risk IDH wt diffuse adult astrocytomas are separable by molecular biomarkers. We have set out our findings in Aibaidula, Ng. Neuro‐oncology 2017. Around the same time, two other groups published findings corroborating our data : Aoki, Natsume. Neuro‐oncology 2018 and Wijnenga, van den Bent. Acta Neuropathologica 2017. It seems that the most appropriate molecular biomarkers to delineate the low and high risk IDH wt astrocytomas will be EGFR, TERTp and 10q. At the time of writing this abstract, we understand the cIMPACT‐now group will soon be publishing an update of the diagnosis of IDHwt astrocytomas largely based on the findings of these papers.

Oral 2: O2‐1

Novel control mechanism of H3K27me3 by mTOR complexes

Mio Harachi; Kenta Masui; Noriyuki Shibata

Pathology 1, Tokyo Women's medical university

Introduction: GBM (glioblastoma) is the most common and deadly human primary brain tumor and it is urgent to reveal the detailed mechanism related to pathological conditions in GBM cell. In recent years, epigenetics has been reported to be important in many types of cancers, but the key factors which cause epigenetic changes in cancer remain to be clarified.

Methods: We used the human GBM cell line U87 with active EGFR mutation (EGFRvIII) as a GBM model and investigated the factors which control epigenetics.

Results: In human glioblastoma tissues and cell lines, high expression of tri‐methylated lysine at 27 on Histone H3 (H327me3) was observed in tumors with EGFRvIII in comparison with those with wildtype EGFR. H3K27me3 has been known as the important epigenetic mark to regulate various genes by remodeling the chromatin structures. We investigated the detailed mechanism to regulate H3K27me3 downstream of EGFR and found that mTORC1 increases the translation of H3K27‐specific methyltransferase EZH2, and mTORC2 promotes H3K27me3 by controlling the production of methylation donor substrate SAM (S‐adenosylmethionine).

Conclusion: Downstream of EGFR signaling, H3K27me3 is cooperatively controlled by two mTOR complexes. This mechanism is expected to be a new therapeutic target against cancer cell.

O2‐2

Comparison of the Gene Expression in Gliosarcoma versus Glioblastoma and Other Astrocytoma Variants

Francia Victoria Abarcar De Los Reyes

Pathology Laboratory, University of the East Ramon Magsaysay Memorial Medical Center

Introduction: Gliosarcoma (GS) is a very rare primary mixed tumor of the CNS, which presents with a biphasic pattern of glial and malignant mesenchymal elements. In contrast, glioblastoma multiforme (GBM) is a malignant primary brain tumor with astrocytic differentiation that comprise as much as 60% of astrocytic neoplasms. The aim of this study is to show the difference in the mutated genes and the copy number alteration expressed in Gliosarcoma versus in GBM using the data provided by The AACR Project GENIE Consortium, under the AACR Project GENIE: Powering Precision Medicine Through An International Consortium, in preparation.

Methods: The difference in the mutated genes and copy number alteration between GS and other groups of astrocytoma is analyzed to establish a targetable gene among these groups for therapeutic purposes.

Results: There is a difference in the frequency of gene expression of the same mutated genes between GS and GBM as well as between GS and the other astrocytoma variants (p>0.00001), but not between GBM and anaplastic astrocytoma, the WHO grade II astrocytoma. The number of accumulated gene mutations in each classification also significantly differs.

Conclusion: Information on the difference in the mutated gene expression of GS versus GBM allows for future evaluation of genes that may serve as potential therapeutic targets in GS that is distinct from GBM.

Poster Session 1: P1‐1

The boundaries and essence of anti‐MOG syndrome

Lei Liu¹; Yueshan Piao²; Jiawei Wang^1,3

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Pathology, Xuanwu Hospital, Capital Medical University; ³Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: Myelin‐oligodendrocyte glycoprotein (MOG) is a specific antigen on the outer surface of myelin sheaths. During recent years, MOG antibodies have been increasingly described in pediatric acute disseminated encephalomyelitis, optic neuritis, aquaporin‐4 antibodies negative neuromyelitis optics spectrum disease (NMOSD) and even autoimmune encephalitis. However, the demographic and clinical boundaries of anti‐MOG syndromes are ever changing. And its pathological alterations are also rarely described.

Methods: Case reports and review of the literatures.

Results: Case 1: Retrospective serum and CSF analyses confirmed MOG antibodies in a 63‐year‐old female patients with 17 clinical episodes (optic neuritis 13 times, brainstem involvement twice and myelitis twice) during 15 years. This case was compatible with aquaporin‐4 antibodies negative NMOSD.

Case 2: An 83‐year‐old male patient developed bilateral blurred visions, paresis of lower extremities and bladder dysfunction within a week. MRI showed multiple optic nerve, brain and spinal cord lesions. His clinical and radiological features also fulfilled clinical diagnostic criteria of aquaporin‐4 antibodies negative NMOSD. Retrospective serum analysis confirmed MOG antibodies.

Case 3: A 39‐year‐old female present in department of neurosurgery for a left parietal lesion with mass effect. Due to concerns of a neoplastic process, a biopsy was undertaken.Neuropathology showed active T cell dominant inflammatory demyelination with proliferation of astrocytes and relative preservation of axons.

Conclusions: Anti‐MOG syndrome can present with dozens of relapses and developed in elderly patients over 80 years old. Its associated demyelinating disorders pathologically mimic multiple sclerosis and distinct from aquaporin‐4 antibodies positive NMOSD.

P1‐2

MS lesion characteristics in Netherlands Brain Bank autopsy cohort: clinical and genetic correlates

Nina L Fransen¹; M. R. Mizee¹; J. Smolders¹; C. G. van Eden¹; S. Luchetti¹; J. B. A. Crusius²; M. R. J. Mason¹; I. Huitinga¹

¹Dept. of Neuroimmunology, The Netherlands Institute for Neuroscience; ²Dept of Immunogenetics, VU University Medical Centre

Introduction: We aim to better understand the pathogenic mechanisms underlying the substantial clinical heterogeneity seen in Multiple Sclerosis (MS), which currently remains largely unknown. Therefore we have studied the clinical and genetic correlates of MS lesion characteristics in the Netherlands Brain Bank MS autopsy cohort.

Methods: From 182 MS brain donors, 3188 tissue blocks containing 7562 MS lesions were dissected. Lesion demyelinating and inflammatory activity were visualized by immunohistochemistry for PLP and HLA‐DR‐DQ. Lesions were classified into active, mixed active/inactive, inactive or remyelinated, microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS‐6. Donors were genotyped for 83 SNPs that were associated with clinical disease severity in GWAS studies and 22 SNPs in genes associated with MS lesion characteristics.

Results: We found that despite a relatively long mean disease duration of 28.6±13.3 years (mean±SD), active or mixed active/inactive lesions were present in 78% of all patients. Patients that had a more severe disease course showed a higher proportion of mixed active/inactive lesions (p=6e‐06) and a higher lesion load (p=2e‐04). Five SNPs showed a significant association with the proportion of active MS lesions or cortical grey matter lesion incidence.

Conclusion: MS lesion activity is substantial in progressive MS and correlates with clinical disease severity. Moreover, disease severity‐linked genotypes correlate with higher proportions of active lesions. With these findings we begin to translate genotypic information into pathogenic mechanisms, which may facilitate the development of personalized therapeutic approaches in MS.

P1‐3

Perivenous inflammatory demyelination is the prominent pathology in myelin oligodendrocyte glycoprotein antibody‐associated disease

Yoshiki Takai¹; Misu Tatsuro^1,2; Kaneko Kimihiko¹; Norio Chihara³; Kouidhi Narikawa⁴; Satoko Tsuchida⁵; Hiroya Nishida⁶; Takahashi Toshiyuki⁷; Masashi Aoki¹; Fujihara Kazuo⁸

¹Department of Neurology, Tohoku University School of Medicine; ²Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine; ³Department of Neurology, Kobe University Graduate School of Medicine; ⁴Department of Neurology, Japanese Red Cross Ishinomaki Hospital; ⁵Department of Pediatrics, Japanese Red Cross Akita Hospital; ⁶Department of Pediatrics, Tokyo Metropolitan Neurological Hospital; ⁷Department of Neurology, Yonezawa National Hospital; ⁸Department of Multiple Sclerosis Therapeutics, Fukushima Medical University

Introduction: Conformation‐sensitive antibodies (Ab) against myelin oligodendrocyte glycoprotein (MOG) is detectable in a proportion of patients with inflammatory demyelinating diseases including optic neuritis, acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica. Meanwhile typical multiple sclerosis (MS) is essentially negative for MOG‐Ab. In several case reports on biopsied brain lesions in patients with MOG‐Ab, the lesions were characterized by T‐cell plus antibody‐mediated demyelination (pattern II MS lesions). However, it is unclear whether MOG‐Ab‐associated demyelinating plaques show sharply demarcated confluent demyelination as seen in MS.

Methods: We immunohistochemically analyzed biopsied brain tissues from five patients with MOG‐Ab in our cohort.

Results: The patients’ median age at onset was 24 years‐old (range 9‐64) and the median interval from onset to biopsy was 1 (range 0.5‐2) month. The clinically diagnoses were ADEM in two, multiple brain lesions without encephalopathy in two and leukoencephalopathy in one. All brain biopsies were performed before acute phase treatment. Pathologically, perivascular cuffings with T cells and macrophages were conspicuous in all cases. B cell infiltration was also observed in three. ADEM‐like multiple perivenous demyelinating lesions were seen in all cases, and the case with leukoencephalopathy had confluent demyelinated lesions as well. Loss of MOG staining was relatively more remarkable compared to other myelin protein stainings. Varied deposits of complement and immunoglobulin were found around some blood vessels and myelin sheath.

Conclusions: Our study suggests that ADEM‐like perivenous inflammatory demyelination with variable cellular and humoral immune reactions is the prominent pathology in MOG‐Ab‐associated demyelinating disease.

P1‐4

Multifocal central nervous system demyelination in a 40 year old: is it paraneoplastic?

Rajalakshmi Poyuran¹; Sajith Sukumaran²; Bejoy Thomas³

¹Department of Pathology, SCTIMST, Trivandrum, Kerala, India; ²Department of Neurology, SCTIMST, Trivandrum, Kerala, India; ³Department of Imaging Sciences and Intervention Radiology, SCTIMST, Trivandrum, Kerala, India

Introduction: Etiologies for central nervous system demyelination are diverse and diagnosing them can be challenging.

Clinical summary: A 40 year old male presented with gait ataxia and dysarthria of 3 months duration. In spite of steroid therapy for suspected demyelinating disorder, he worsened with lower limb weakness and urinary retention. MRI showed multiple non‐enhancing T2/FLAIR hyperintensities in bilateral cerebellum and frontal lobes with a short enhancing lesion in spinal cord at T4‐T5. CSF study showed lymphocyte predominant pleocytosis (15cells/mm³,90% lymphocytes), mildly elevated proteins (98mg/dl) and normal sugar. CSF and serum were positive for oligoclonal bands and serum negative for Aquaporin‐4 antibody. Work‐up for vasculitis, infection (fungal, tuberculosis, toxoplasmosis, etc) and malignancy was negative. Plasma exchange was initiated, however he developed sepsis and succumbed.

Pathological findings: At autopsy, cerebral hemispheres were mildly atrophic. Coronal sections showed softened white matter around bilateral occipital horns and in corpus callosum. Microscopically, multiple small, well‐defined to confluent foci of demyelination were noted in frontal, occipital and cerebellar white matter. All the lesions appeared to be of similar age and were associated with mild perivascular CD8‐predominant T‐lymphocytic infiltration. Spinal cord white matter was focally rarefied. There was no evidence of metachromatic material, viral inclusion, vasculitis or neoplasm. Immunohistochemistry for JC virus, measles and toxoplasma were negative. Examination of other organs showed a latent papillary microcarcinoma in the thyroid gland.

Conclusion: CNS demyelination as a paraneoplastic phenomenon is uncommon and very rarely has been reported with papillary thyroid carcinoma. Could this case be a paraneoplastic phenomenon?

P1‐5

The antidepressant effect of ketamine in a murine model of neuroinflammation involves the modulation of microglial activation

F Verdonk^1,2; G Jouvion¹; A Danckaert^1,3; G Ferreira de Medeiros¹; R Gaillard^1,4,5; F Chrétien^1,5,6

¹Experimental neuropathology, Institut Pasteur, Paris, France; ²Departement of Anesthesiology and Intensive Care, Saint Antoine Hospital, Paris, France; ³UTechS Photonic BioImaging‐Citech, Institut Pasteur, Paris, France; ⁴Service Hospitalo Universitaire, Centre Hospitalier Sainte‐Anne, Paris, France; ⁵Paris‐Descartes University, Sorbonne University, Paris, France; ⁶Neuropathology Department, CH Sainte‐Anne, Paris, France

Introduction: Depression is a severe condition that represents a major public health issue. Current therapies, targeting primarily monoaminergic neurotransmission systems, are partially ineffective due to their long response time and low remission rates. Studies have demonstrated a link between neuroinflammation and depression. Ketamine, an NMDA antagonist, has recently risen as a novel therapy to treat depression, notably in chemically resistant depressive patients. Recent studies suggest that ketamine might exert its effects through immunomodulating properties.

Methods: In a LPS‐induced depressive‐like behavior using a mutant mouse model (CX3CR1^GFP/+ mice with fluorescent microglial cells), we carried out a combination of two complementary approaches: clinical (behavioral tests) and functional associating morphological (histology/morphometry techniques combined with automatized 3D confocal microscopy allowing fine analysis of microglial cells morphology/reactivity), phenotypical and proteomic characteristics.

Results: We demonstrate that a single dose of ketamine attenuates and restores the LPS‐induced depressive‐like behavior at multiple levels: i/ by reversing anhedonia and anxiety at a behavioral level, ii/ by decreasing the levels of pro‐inflammatory cytokines and by shifting the microglial immuno‐phenotype to M2a in preference to M1 and M2b and iii/ by reducing the microglial morphological alterations induced by LPS injection.

Conclusion: Taken together, these data show that ketamine might have its antidepressant effect mediated by an anti‐inflammatory action on microglia cells.

P1‐6

Immunophenotype of lymphocytic primary angiitis of the central nervous system: a case study.

Masashi Watanabe¹; Soichi Kondo¹; Shiro Ohue²; Katsumi Kito³; Toru Iwaki⁴; Kensho Okamoto¹

¹Department of Neurology, Ehime Prefectural Central Hospital, Matsuyama, Japan; ²Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Japan; ³Department of Pathology, Ehime Prefectural Central Hospital, Matsuyama, Japan; ⁴Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Introduction: The reports on immunohistochemical profiles about primary angiitis of the central nervous system (PACNS) are scant. Here we report a lymphocytic PACNS case.

Clinical summary: A 31‐years‐old man without past medical history fell down suddenly and showed generalized seizure for a few minutes. Neurological examinations showed only amnesic aphasia. Brain MRI revealed multiple cortical and subcortical high intensity lesions in the left temporal and occipital lobes on FLAIR and T2‐weighted images, many of which presented with small ring‐enhancement. Cerebral angiography showed no significant regional stenosis. Blood investigations showed no findings with suspected neither inflammatory, infectious, nor collagen diseases. Cerebrospinal fluid analysis indicated mild increased protein concentrations with elevation of IL‐6, anti‐glutamate receptor antibodies, and granzyme B. Brain biopsy revealed lymphocytic vasculitis compatible with PACNS. Treatment with prednisolone and cyclophosphamide resolved both his clinical features and abnormal MRI findings.

Pathological findings: Hematoxylin and eosin staining showed marked infiltration of lymphocytes without evidence of atypia and monoclonality, presenting with stenosis of arterioles in the cerebral parenchyma and meninges. Immunohistochemistry for lymphocytic markers revealed that CD3‐positive T cells, which mainly consist of CD8‐positive T cells, and CD20‐positive B cells obviously infiltrated in the vessel wall and perivascular space, but randomly in the cerebral parenchyma. CD138‐positive cells were not detected anywhere.

Conclusion: Although the number of literatures showing the immunophenotypes of PACNS are limited, a mixed population of CD8‐positive T cells and CD20‐positive B cells in the affected vessels and brain tissue may be one of the common characteristics of lymphocytic PACNS.

P1‐7

Brain biopsy findings in a patient with MOG antibody‐associated encephalitis

Takayuki Kosaka¹; Yoichiro Nagao¹; Makoto Nakajima¹; Jun‐Ichiro Kuroda²; Kimihiko Kaneko³; Toshiyuki Takahashi⁴; Hajime Miyata⁵; Akiyoshi Kakita⁶; Yoshiki Mikami⁷; Yukio Ando¹

¹Department of Neurology, Graduate School of Medical Sciences, Kumamoto University; ²Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University; ³Department of Neurology, Tohoku University Graduate School of Medicine; ⁴Department of Neurology, Yonezawa National Hospital; ⁵Department of Neuropathology, Research Institute for Brain and Blood Vessels – AKITA; ⁶Department of Pathology, Brain Research Institute, Niigata University; ⁷Department of Diagnostic Pathology, Kumamoto University Hospital

Introduction: Myelin oligodendrocyte glycoprotein (MOG) is a protein expressed on the surface of myelin sheath and oligodendrocyte. Pathological findings in patients with MOG antibody‐associated encephalitis have, however, rarely been described to date.

Clinical summary: A 44‐year‐old Japanese male developed fever and mild aphasia followed by impaired consciousness, agnosia, hiccup and urinary retention. Brain MRI revealed a Gd‐enhancing mass lesion in the left frontal white matter. Cerebrospinal fluid analysis demonstrated lymphocytic pleocytosis on cytology and oligoclonal bands. Neoplastic conditions were unlikely on brain biopsy performed on Day 33 after onset. Clinico‐radiological findings improved gradually after methyl‐prednisolone pulse therapy followed by oral prednisolone. Thereafter, anti‐MOG‐antibodies turned out to be positive.

Pathological findings: Microscopically, glioneuronal tissue showed microvacuolation with reactive gliosis in addition to perivascular and parenchymal lymphocytic inflammation, associated with histiocytic reaction predominantly composed of CD68‐positive activated microglia in the parenchyma. Lymphocytes were predominantly composed of CD8‐positive T‐lymphocytes located in perivascular spaces. CD20‐positive B‐cells were confined to the perivascular spaces. Neither demyelinating lesions nor myelin laden macrophages were observed. Immunoreactivity for activated complement (C9neo antigen) was not detected.

Conclusions: Pathological findings of MOG antibody‐associated encephalitis were reported. A major findings were vacuolar change with T‐cell dominant inflammation without typical demyelination, which were distinct from the previously reported findings such as T‐cell‐mediated inflammation with complements‐associated demyelination. This case indicates the MOG antibody‐related disease might be a heterogeneous in terms of pathophysiology.

P1‐8

The pathological features of MOG antibody‐positive cerebral cortical encephalitis as a new spectrum associated with MOG antibodies

Toshimasa Ikeda^1,2,3; Kentaro Yamada³; Tatsuro Misu⁴; Ryo Ogawa⁴; Yoshiki Takai⁴; Maya Mimuro¹; Yasushi Iwasaki¹; Kaoru Kamimoto³; Noriyuki Matsukawa²; Mari Yoshida¹

¹Institute for Medical Science of Aging, Aichi Medical University; ²Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences; ³Department of Neurology, Nagoya City East Medical Center; ⁴Department of Neurology, Tohoku University School of Medicine

Introduction: Recently we experienced several adult patients with myelin oligodendrocyte glycoprotein (MOG) antibody‐positive cerebral cortical encephalitis, whose clinical characteristics were different from the demyelinating disease associated with anti‐MOG antibodies, including acute disseminated encephalomyelitis and aquaporin‐4 seronegative neuromyelitis optica spectrum disorders. Here, we present the first pathology before immune therapy in an adult patient with MOG antibody‐positive cerebral cortical encephalitis.

Clinical summary: A 29‐year‐old healthy Japanese woman experienced generalized tonic seizure with an oedematous, FLAIR high‐intensity lesion involving the right parietal cortex on the brain MRI. After a brain biopsy we found her serum anti‐MOG antibodies positive. She underwent a full recovery with steroid therapy, and her anti‐MOG antibody finally became negative.

Pathological findings: A brain biopsy revealed mild inflammatory changes in the cortex and subcortex without distinct demyelination, although previous pathological reports with anti‐MOG antibodies showed typical demyelination. There was the limited loss of MOG immunoreactivity accompanied by microglial proliferation in perivascular regions and the subcortical white matter in a patchy manner.

Conclusion: From this case, we speculate that MOG antibody‐positive cerebral cortical encephalitis may be clinicopathologically different from the well‐known demyelinating disease. We propose that this disease will be a new spectrum associated with anti‐MOG antibodies.

P1‐9

Chronic leukoencephalopathy‐like disease expansion and massive necrosis of the cerebral white matter in a patient with neuromyelitis optica

Chiho Ishida¹; Tokuhei Ikeda¹; Kiyonobu Komai¹; Kazuya Takahashi¹; Moeko Noguchi‐Shinohara²; Masahito Yamada²

¹Department of Neurology, Hokuriku Brain and Neuromuscular Disease Center, National Hospital Organization Iou Hospital; ²Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences

Introduction: We describe an autopsy case of a patient with neuromyelitis optica (NMO) who exhibited a unique pattern of disease progression with regard to whit matter lesions.

Clinical summary: We report the case of a woman with NMO who exhibited bilateral optic neuritis, longitudinally extensive myelitis, serum anti‐aquaporin 4 (AQP4) antibodies. The disease duration was 26 years, and the patient died at the age of 65. Sequential magnetic resonance images revealed leukoencephalopathy‐like lesions extending symmetrically and contiguously from the periventricular regions, which had begun to transform into multiple cavities with semi‐annular partitions.

Pathological findings: On autopsy, the patient's brain weighed 985g. The periventricular and cerebellar white matter were necrotic, with semi‐annular partitions characterised by demyelination and fibrillary giosis. Severe loss of the ependymal linings adjacent to the lateral ventricles was observed, along with gliosis and AQP4‐hyperreactivity, AQP4‐immunoreactiviey was partially decreased in the remaining ependymal cells. AQP4‐immunonegative, glial fibrillary acidic protein (GFAP)‐immunonegative, and myelin basic protein (MBP)‐immunopositive lesions were observed in the cerebral white matter surrounding the necrotic lesions. The cervical and thoracic regions of the spinal cord were severely atrophic, exhibiting longitudinal central necrosis and blood vessel hyalinisation. Lymphocyte infiltration was observed surrounding the vessels in the sacral cord. There were no vasculitic changes in the vessel walls of the general organs or central nervous system.

Conclusion: These neuropathological abnormalities corresponded to those described in previous reports regarding NMO lesions. Our findings indicate that expansive, chronic leukoencephalopathy‐like lesions can be observed in patients with NMO.

P1‐10

Five cases of cerebral amyloid angiopathy related inflammation/angiitis diagnosed with brain biopsy.

Hideyuki Moriyoshi^1,2; Soma Furukawa¹; Aya Ogura^1,2; Yasuhiro Ito¹; Mari Yoshida³; Masahisa Katsuno²

¹Department of Neurology, TOYOTA Memorial Hospital; ²Department of Neurology, Nagoya University Graduate School of Medicine; ³Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: Cerebral amyloid angiopathy‐related inflammation/angiitis (CAA‐RI) is rare inflammatory disease of the central nervous system, associated with the clinical symptoms include subacute cognitive impairment or seizure. High diagnostic accuracy was reported with a small pathologic series, however, the pathological spectrum of CAA‐RI is still unknown. We investigated the findings of brain biopsy of 5 patients with CAA‐RI to evaluate the inflammatory response and the effect of treatment.

Materials and methods: The average age of patients was 68.4 (53‐80). All patients were men. Initial symptoms were subacute progressive dementia (3), seizure (1) and left sided motor dysfunction (1). Most patients had cerebral microbleeds, focal subarachnoid hemorrhage, asymptomatic small infarction and leptmeningeal enhancement on head MRI. We diagnosed all patients as CAA‐RI with brain biopsy and treated them with corticosteroid 1mg/kg/day.

Results: We investigated severity of inflammation and Alzheimer Disease (AD)‐related pathology. All patients had severe CAA. Two patients had severe to moderate granulomatous angiitis of subarachnoid and parenchyma artery, but its AD‐related pathology was minimum. Other 3 cases had mild inflammation around its subarachnoid and parenchyma arteries associated with moderate to severe AD related pathology. The effect of corticosteroid therapy was more prominent in 2 patients with severe to moderate granulomatous angiitis.

Conclusion: Clinical symptom and pathologic severity of CAA‐RI were various. The effect of corticosteroid therapy was related to pathologic findings. Severity of inflammation and concomitant AD related pathology appears associated with the responsiveness of treatment. CAA‐RI could also influence the clinical course of AD.

P1‐11

MOG antibody positive meningo‐leukoencephalitis with demyelination

Kentaro Tokumoto^1,2; Ryoko Takeuchi¹; Kimihiko Kaneko³; Toshiyuki Takahashi^3,4; Shigeo Murayama²; Toshio Fukutake¹

¹Department of Neurology, Kemeda Medical Center; ²Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ³Department of Neurology, Tohoku University School of Medicine; ⁴Department of Neurology, National Hospital Organization Yonezawa Hospital

Introduction: Myelin oligodendrocyte glycoprotein (MOG) antibodies are found in pediatric patients with demyelinating disease and patients with aquaporine 4 antibody‐negative neuromyelitis optica spectrum disorders. Recently MOG antibodies have been identified in some patients with cerebral cortical encephalitis with epilepsy. In a report of similar case, brain biopsy revealed brain edema and perivascular cuffing. Myelin sheaths were preserved. The pathogenic roll of MOG antibody in this cortical involvement remains unclear.

Clinical Summary: A 21 year‐old man presented with repeated left‐side motor seizures and progressive left hemiparesis. His brain MRI showed fluid attenuation inversion recovery (FLAIR) hyper‐intensities involving the cortex and subcortical white matter of the right frontal, parietal and left medial parietal lobe, with gadolinium‐enhancement along the sulci. After admission he developed bilateral optic neuritis. Brain biopsy was performed and pathological diagnosis during surgery was meningoencephalitis. Treatment with corticosteroids was started and he responded well. Retrospective analysis of the serum and cerebrospinal fluid confirmed to be positive for MOG antibodies.

Pathological findings: Brain biopsy revealed inflammatory cell infiltration with lymphocytes and neutrophils of subarachnoid space and cerebral cortex. Myelin sheaths were preserved in some biopsy samples. The other sample of subcortical white matter showed a demyelinating lesion with foamy macrophages. Axons were relatively preserved in the same area.

Conclusion: Demyelination was observed in our patient with MOG antibody‐positive cerebral cortical encephalitis. This finding favors the hypothesis of direct pathogenicity of MOG antibodies.

P1‐12

DNA double‐strand breaks in oligodendrocytes ‐ the unifying step prior to myelin degeneration in Alzheimer's dementia and multiple sclerosis

Kai‐Hei Tse^1,2; Julia Kofler³; Antony J Harding²; Michael E Buckland²; Karl Herrup¹

¹Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong; ²MS Research Australia Brain Bank, Department of Neuropathology, Royal Prince Alfred Hospital & Brain and Mind Center, University of Sydney, Sydney, NSW, Australia; ³Division of Neuropathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Introduction: Myelin degeneration is one of the earliest structural changes in the human ageing brain. Such pathology is obvious in frontal lobe and exacerbated in cognitive impairments. We have previously shown that DNA damage, but not amyloid deposition, is associated with oligodendrocyte loss in Alzheimer's dementia(AD). Here, we further hypothesize that genomic injury with DNA double‐strand breaks(DSBs) in oligodendrocytes is the initiating cellular pathology prior to myelin loss in the canonical demyelinating disease, multiple sclerosis(MS).

Methods: To test, oligodendrocytes and their DSBs burden in the frontal cortices were studied using immunohistochemistry. Three cohorts of postmortem specimens, including sporadic AD (n=29), familial AD (n=7), multiple sclerosis (n=12) and their age‐matching controls were examined. To confirm, RNA‐seq databases of oligodendrocyte differentiation and MS lesions(GEO‐NCBI) were queried. The effects of DSBs on oligodendrocytes was experimentally tested at their distinct stages of differentiation using primary cell culture.

Results: While histological quantifications are being completed, our preliminary results revealed the deposition of DSBs, marked by nuclear 53BP1 foci, in the oligodendrocyte in different frontal cortices. Our meta‐analysis of oligodendrocytes RNA‐seq datasets showed profound negative correlations between myelin and DNA repair gene expression. In cell culture, DNA damaging reagent, etoposide, attenuates proliferation and inhibits maturation of oligodendrocyte progenitor cells, while it induces aberrant cell cycle re‐entry and apoptosis in myelin‐forming post‐mitotic oligodendrocytes.

Conclusion: The present work is underway, but our preliminary data supports the hypothesis that oligodendrocytes are highly susceptible to DNA damage, and such DSBs could be a pathological marker in demyelinating conditions.

P1‐13

Diaschisis in the experimental white matter stroke model: Histopathology and pathogenesis

Min‐Cheol Lee¹; Kyung‐Wha Lee¹; Hanlim Song²; Ji‐Young Park²; Hyoung‐Ihl Kim²

¹Department of Pathology, Chonnam National University Medical School; ²Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology

Introduction: Cerebral functional insufficiency in stroke might be due to pathologic changes of the primary focal lesion as well as metabolic depression in brain areas remote from initial ischemic lesion, i.e. diaschisis. Previously, we showed that the development of diaschisis lesions by FDG‐microPET study in a rat model of experimental photothrombotic infarct of the internal capsule. In the present study we hypothesized that the reduced neuronal and synaptic activities in the diaschisis lesion can be caused by the inhibitory action of GABA.

Methods: Tissue obtained from diaschisis lesions, focused by FDG‐microPET image, studied by light and electron microscopy, especially immunostains for GFAP, neurofilament protein and GABA. Metabolic change of GABA synthesis checked using a reversible inhibitor of MAO‐B, named KDS2010.

Results: Experimental brain displays focal diaschisis lesions in the ipsilateral cortex at day 7 after ischemic insults. The lesions are sustained for more than 2 weeks, and evidenced by significantly increased cortical diaschisis volume. Tissue obtained from diaschisis in the motor cortex reveals atrogliosis and minimal pathologic changes of neuron; swollen dendrites and multi‐vacuolar degeneration of neuropils. Significantly decreased volume of cortical diaschisis with recovery of glucose metabolism in the primary motor cortex observed by administration of KDS2010. No significant alteration of neuronal GABA present.

Conclusion: The histopathologic change and hypometabolic state of diaschisis possibly caused by astrocytic GABA suppression. MAO‐B could be the key enzyme for the pathogenesis of diaschisis.

P1‐14

White matter neuropathology due to cerebral micro‐hemorrhages in geriatric traumatic brain injury

Kenneth A Rostowksy; Alexander S Maher; Nahian F Chowdhury; Andrei Irimia

Ethel Percy Andrus Gerontology Center, Leonard Davis Schoo of Gerontology, University of Southern California

Introduction: The clinical significance of neuropathology associated with cerebral microbleeds (CMBs) due to mild traumatic brain injury (mTBI) remains unclear. Here we use magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and connectomic analysis to investigate the statistical association between mTBI‐related CMBs, post‐TBI changes to the human connectome and neurological/cognitive deficits.

Methods: 26 (13 females) geriatric mTBI victims and 26 (13 females) age‐ and sex‐matched healthy control (HC) volunteers were recruited. MRI and DWI volumes were acquired and, for each peri‐lesional DTI streamline bundle, the null hypothesis implied no neurological or cognitive deficit associated with between‐scan differences in the mean fractional anisotropy (FA) of DTI streamlines within each bundle. Results

In HC volunteers, the analysis failed to identify significant differences in the mean FA of DTI streamline bundles. In the mTBI group, significant differences were found in 21 out of 26 volunteers. In those volunteers where significant differences had been found, these differences were associated with an average of about 47% of all identified CMBs (sigma = 21%). In 12 out of the 21 volunters exhibiting significant FA changes, cognitive functions (memory acquisition and retrieval, top‐down control of attention, planning, judgment, cognitive aspects of decision‐making) were found to have deteriorated over the six months following injury (r = ‐0.32, p < 0.001).

Conclusion: Our preliminary results suggest that acute mTBI vascular neuropathology may be associated with cognitive decline in some mTBI patients. Future research should attempt to identify mTBI patients at high risk for cognitive sequelae.

P1‐15

Upregulation of annexin A1 in reactive astrocytes at the boundaries of human brain infarcts

Masahiro Shijo^1,2; Masaki Tachibana²; Tetsuro Ago²; Takanari Kitazono²; Hiroyuki Honda¹; Satoshi O Suzuki¹; Toru Iwaki¹

¹Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University; ²Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University

Introduction: Annexin A1 (ANXA1) is mainly expressed in astrocytes and ependymal cells of normal human brains. Regarding acute ischemic brain, increased expression of ANXA1 in microglia and vascular endothelium has been shown with rodent models; however, astrocytic expression of ANXA1 in infarcted brain tissues has been little focused on.

Methods: We performed immunohistochemistry in autopsied human brain tissues from 15 cases with cerebral infarction, and the brain tissues of CB‐17 mouse stroke model generated by occlusion of the middle cerebral artery.

Result: Marked expression of ANXA1 was noted in the viable regions adjacent to necrosis. ANXA1 was mainly distributed in astrocytes rather than microglia at the viable boundary area, as well as in macrophages and endothelium at the necrotic area. Compared with the area of fibrillary gliosis revealed by GFAP, ANXA1‐immunopositive area was restricted in the narrow band of viable periinfarct region. TMEM119‐immunopositive resident microglia gathered in the periphery of necrosis, but this population was decreased in the ANXA1‐immunopositive periinfarct areas. ANXA1 expression in microglia, macrophages and endothelium was also noted in the mouse ischemic brains, however, astrocytic ANXA1 was not observed regardless of the duration of ischemia.

Conclusion: ANXA1 expression was elevated in reactive astrocytes around necrosis during acute ischemia of human brains. Astrocytic ANXA1 could affect the behavior of resident microglia through the strong anti‐inflammatory properties. The act of ANXA1 during focal brain ischemia might be different between human and mouse species.

P1‐16

A case of juvenile central nervous system venulitis mimicking multiple sclerosis

Hitomi Onomura¹; Katsuhiko Kunitake²; Ryosuke Inagaki²; Soma Furukawa²; Junichiro Suzuki²; Suguru Nishida²; Satoshi Kitagawa³; Mari Yoshida⁴; Yasuhiro Ito²

¹Division of Integrated Medicine, TOYOTA Memorial Hospital; ²Department of Neurology, TOYOTA Memorial Hospital; ³Department of Clinical Laboratory, TOYOTA Memorial Hospital; ⁴Institute for Medical Science of Aging, Aichi Medical University

Introduction: Central nervous system vasculitis is rare but could be a life‐threatening disease

Clinical summary: The patient is a 17‐year‐old female with transient sudden weakness and dysesthesia on the right side, associated with headache and nausea. On examination, head MRI presented white matter lesions confined to the left hemisphere. Cerebrospinal fluid showed no specific findings, negative for oligoclonal bands. Screening bloodwork, including C‐reactive protein and thyroid function, were normal. Extensive hematologic, infectious and autoimmune disease work‐up were negative. Steroid pulse therapy was performed in suspect of multiple sclerosis. Fingolimod hydrochloride was administered 140 days after primary onset. At day 267, she again felt transient hypesthesia. Cranial MRI showed expansion of the high infiltrated areas of the left hemisphere on FLAIR and T2WI, accompanied with edema. Multiple contrasted areas were also observed. ECD‐SPECT showed decreased accumulation in the left hemisphere.

Pathological findings and treatment: Brain biopsy revealed lymphocytic, non‐granulomatous inflammation in and around the vessels, especially in the venules of the subarachnoidal space. Lymphocytes were mostly T cells. Immune suppressive treatment including mPSL 1000 mg/day pulse therapy was induced. Her clinical symptoms and neuroradiologic abnormalities ameliorated. She is now followed by oral PSL 10 mg/day and azathioprine 100 mg/day.

Conclusion: We experienced an extremely rare case of juvenile CNS isolated venulitis. Only a few cases are reported in this category. This case emphasizes the importance of brain biopsy in determining diagnosis and decision of treatment.

P1‐17

Cerebral impact of muscle trauma

Lorna Gueniot^1,2,3; Victoria Lepere^1,4,5; Anne Danckaert^1,6; Gabriela Ferreira de Medeiros¹; Olivier Langeron^1,4,5; Fabrice Chretien^1,7,8; Gregory Jouvion¹

¹Experimental neuropathology, Institut Pasteur, Paris, France; ²Direction Generale de l Armement, Ministere des Armees, Paris, France; ³ED Bio‐SPC, Paris‐Descartes University, Paris, France; ⁴Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitie‐Salpetriere Hospital, Assitance Publique‐Hopitaux de Paris, Sorbonne University, Paris, France; ⁵Polyvalent Surgical Resuscitation, La Pitie‐Salpetriere Hospital, Assitance Publique‐Hopitaux de Paris, Sorbonne University, Paris, France; ⁶UTechS Photonic BioImaging‐Citech, Institut Pasteur, Paris, France; ⁷Neuropathology Department, CH Sainte‐Anne, Paris, France; ⁸Paris‐Descartes University, Sorbonne University, Paris, France

Introduction: Mechanical trauma is the fifth cause of death on earth and the first cause of reduced life expectancy in young population, with many permanent sequelae. Among them, neurological impairments are the most serious and disabling. Well documented in sepsis and head trauma, the scientific literature remains poor regarding peripheral muscle trauma alone. Our aim is to characterize the immediate and long‐term brain repercussion, on different aspects: clinical (behavorial and cognitive alterations), tissular (neuro‐inflammation) and cellular (microglia reactivity).

Methods: Using a mutant mouse model (CX3CR1^GFP/+ mice with fluorescent microglia cells), we carried out a combination of two complementary approaches: clinical (behavioral tests) and morphological (histology/morphometry techniques combined with automatized 3D confocal microscopy allowing fine analysis of microglia cells morphology/reactivity).

Results: Peripheral muscle trauma has a major impact on central nervous system:

‐ at an early stage after muscle trauma: microglial cells demonstrate a reactivity in several brain areas, and more specifically in the hippocampus with an increase of microglial complexity within the first 24 hours

‐ at a late stage, after muscle regeneration: mice have an impaired memorization of a new object, despite no alteration of locomotion and anxiety.

Conclusion: Central nervous system‐related sequelae have to be considered in any context of trauma, even when the brain is not directly involved. Thus, a muscle lesion can initiate durable cognitive disorders.

P1‐18

Coexistence of transthyretin‐ and Aβ‐type cerebral amyloid angiopathy in a patient with hereditary transthyretin V30M amyloidosis

Kenji Sakai¹; Miwako Asakawa¹; Ryoichi Takahashi¹; Chiho Ishida²; Ritsuko Nakamura³; Tsuyoshi Hamaguchi¹; Kenjiro Ono^1,4; Kazuo Iwasa¹; Masahito Yamada¹

¹Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences; ²Department of Neurology, National Hospital Organization Iou Hospital; ³Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Sciences; ⁴Department of Neurology, Showa University School of Medicine

Introduction: We describe an autopsy case of late‐onset systemic transthyretin (TTR) amyloidosis with a V30M mutation in the TTR gene showing coexistence of TTR‐ and amyloid β (Aβ) ‐type cerebral amyloid angiopathy (CAA).

Clinical summary: An 84‐year‐old man with unremarkable family history developed lower and upper limb weakness, constipation, and anhydrosis at the age of 73. At the age of 77, he received a diagnosis of hereditary systemic TTR amyloidosis with TTR V30M mutation based on TTR‐positive amyloid deposition in the sural nerve and genetic analysis. Oral administration of diflunisal was started; however, his symptoms related to neuropathy and cardiac dysfunction deteriorated. Diflunisal was replaced with tafamidis at the age of 83. He died of heart failure at the age of 84. The total clinical course was 11 years.

Pathological findings: The brain and dura mater showed mild dilatation of the lateral ventricles and weighed 1,355 g before fixation. Microscopically, severe loss of myelinated fibers with TTR‐positive amyloid deposition was demonstrated in the peripheral nerves. The dorsal root ganglia, sympathetic ganglia, skin, and pituitary also demonstrated considerable TTR‐positive amyloid deposition. Leptomeningeal blood vessels throughout the central nervous system and the cerebral cortical blood vessels showed CAA comprising coexistence of TTR‐ and Aβ‐positive amyloid deposition. Interestingly, most of the TTR and Aβ deposited independently on the vessel walls, as analyzed using the double labeling method.

Conclusion: Independent deposition of the TTR and Aβ amyloid on the vessel walls indicate that cross‐seeding of TTR and Aβ is less likely in humans.

P1‐19

Expression of hepatocyte growth factor and c‐Met receptor in the anterior horn cells of the spinal cord in the patients with spinal cord injury

Hiroshi Kohama¹; Yui Akazawa¹; Masahiro Ii¹; Kosuke Yonekura¹; Yuki Kaida¹; Keiko Kato¹; Shinichiro Kitao¹; Masako Kato²; Hiroshi Funakoshi³; Shinsuke Kato¹

¹Division of Neuropathology, Tottori University Faculty of Medicine; ²Division of Molecular Pathology, Tottori University Faculty of Medicine; ³Asahikawa Medical University

Introduction: To clarify the survival mechanism of the residual anterior horn cells for trauma, we investigated the immunohistochemical expression of hepatocyte growth factor (HGF), a novel neurotrophic factor, and its receptor, c‐Met in the residual neurons of spinal cord injury (SCI) patients.

Methods: We examined autopsy specimens of the spinal cords from 10 SCI patients and 10 neuropathologically normal individuals by routine staining and immunohistochemistry using anti‐HGF and anti‐c‐Met antibodies.

Results: In normal subjects, immunoreactivity to both anti‐HGF and anti‐c‐Met antibodies was observed in almost all anterior horn cells of the spinal cords. As for SCI patients, we classified the injured lesions into “complete injury region” and “incomplete injury region” by damage level to spinal cord. In “complete injury region”, no anterior horn cells were recognized in some cases, although some residual neurons were observed in the others. On the other hand, in “incomplete injury region”, all cases had some residual neurons. Almost all residual anterior horn cells immunohistochemically co‐expressed both HGF and c‐Met. In both injured lesions, increasing the immunoreactive intensity of both proteins for residual neurons started by six days after injury in comparison to normal subjects and continued until one month. From one month to four years after injury, immunoreactivity was decreasing to the normal degree.

Conclusion: These results suggest that the HGF‐c‐Met upregulate system by autocrine and/or paracrine is one of the self‐protective systems of the residual anterior horn cells, and HGF‐c‐Met upregulate system in residual anterior horn cells is caused by trauma.

P1‐20

Long‐term interval from the spinal cord lesion to subsequent brain lesion in primary central nervous system vasculitis: a case report

Tomoya Kon^1,2; Yukihisa Funamizu²; Chieko Suzuki²; Aiichiro Kurihara³; Tsugumi Sato⁴; Hidekachi Kurotaki⁴; Akira Kurose⁵; Masahiko Tomiyama²; Koichi Wakabayashi¹

¹Department of Neuropathology, Hirosaki University; ²Department of Neurology, Aomori Prefectural Central Hospital; ³Department of Neurology, Aomori Rosai Hospital; ⁴Department of Pathology, Aomori Prefectural Central Hospital; ⁵Department of Anatomic Pathology, Hirosaki University

Introduction: Primary central nervous system vasculitis (PCNSV) is an uncommon vasculitis restricted to the small‐ and medium‐size vessels in the brain and spinal cord. Previously, only 9 cases have been reported that initially manifested as an isolated spinal cord lesion with subsequent brain involvement, where the longest interval from onset to brain involvement was 1 year and 11 months. We present the case of an isolated spinal cord lesion with subsequent brain involvement appearing 7 years and 5 months later.

Clinical Summary: A 50‐year‐old man presented with progressive walking difficulty and urinary retention. Neurological examination revealed lower legs muscle weakness and spasticity. Spinal MRI revealed high signal intensity on T2 weighted images of the cervical to thoracic cord, and no brain lesions were found. He was diagnosed as having myelitis and treated with steroid therapy, and his symptoms partially resolved. However, after discontinuation of steroid therapy, his leg weakness and spasticity worsened, and 7 years and 5 months later he presented with altered mental status, right temporal lobe lesion was found with brain MRI. A biopsy was performed from the lesion.

Pathological findings: Inflammatory cells infiltrated within and around the vessel walls of leptomeninges and parenchyma, and the lumen of vessels were hypertrophic and stenotic. Immunohistochemically, amyloid β was negative in the vessel walls, and infiltrated inflammatory cells were mostly CD3‐positive T‐lymphocytes. The patient was diagnosed as having PCNSV.

Conclusion: This case demonstrates that a brain lesion can develop after an extended interval from spinal onset in PCNSV.

P1‐21

A case of congophilic amyloid angiopathy‐related hemorrhages versus traumatic brain injury by car accident?

Dennis J Chute¹; Kia K Newman¹; Hajime Miyata²

¹Dutchess County Department of Behavioral and Community Health, Poughkeepsie, NY, USA; ²Department of Neuropathology, Research Institute for Brain and Blood Vessels ‐ AKITA, Akita, Japan

Introduction: Congophilic amyloid angiopathy (CAA) is a known cause of cerebral lobar hemorrhages in the elderly. Precipitation of such hemorrhages may lead to confusion in forensic cases.

Clinical Summary: A 77‐year‐old female restrained driver was involved in a low speed (< 30 miles per hour) car crash. Her car was hit on the front driver's side bumper causing it to rotate and strike a snow bank deploying the airbags. She never lost consciousness, denied hitting her head and exited the car with minimal assistance. She initially refused medical attention and no injuries were appreciated. About 15 minutes later, emergency responders found her flaccid, non‐verbal and leaning toward her left side. Her blood pressure was 180/100 mmHg. A computerized tomography of the head revealed two left cerebral hematomas and bilateral thin subarachnoid hemorrhage with a midline shift from left to right. She died after 6 days.

Pathologic Findings: At autopsy there was no external injury. Internally, there was a left frontal subscalpular hemorrhage. The 1350‐gram‐brain revealed two left frontal hematomas occupying the inferior and middle frontal sulci and neighboring subcortical white matter, showing continuities at bottoms of sulci. The Aβ‐immunopositive severe CAA with microangiopathies was confirmed. No cortical contusions were noted.

Conclusion: The hemorrhagic stroke in this individual appeared to be secondary to CAA‐associated hemorrhage initially in her cerebral cortex or sulcal subarachnoid space with extension into the underlying white matter. The excitement of the car crash appears to have provoked this hemorrhage, not any direct trauma to her head.

P1‐22

A case of Aspergillus infection presenting as cerebral infarction and subarachnoid hemorrhage due to infectious aneurysm rupture

Ryosuke Inagaki¹; Kitagawa Satoshi²; Oeda Motoki³; Nagahisa Shinya³; Kunitake Katsuhiko¹; Furukawa Soma¹; Iwata Mai⁴; Suzuki Jyunichiro¹; Nishida Suguru¹; Ito Yasuhiro¹

¹Department of Neurology TOYOTA Memorial Hospital; ²Department of Clinical Laboratory TOYOTA Memorial Hospital; ³Department of Neurosurgery TOYOTA Memorial Hospital; ⁴Department of Neurology Chutoen General Medical Center

Introduction: Central nervous system aspergillosis is a very poor prognostic disease.

Clinical summary: A 71‐year‐old female, treating chemotherapy for ascending colon cancer stage IV, was admitted to our hospital due to high fever. Antibiotics treatment was started suspecting CV port infection. On the day of hospitalization, movement disorder of the right upper limb was observed. Head MRI showed cerebral infarction on the left side of the pons. MRA did not show any abnormalities including the basilar artery (BA). Thinking of perforating branch infarction, antithrombotic therapy was started. The course of cerebral infarction was good, however sudden consciousness disturbance occurred on the 7th day. Cranial CT and 3D‐CT angiography showed subarachnoid hemorrhage (SAH) and newly developed aneurysm at the BA. Emergency endovascular surgery by coil embolization was performed. Extravasation was observed during the coil embolization. Hydrocephaly was recognized with head CT after embolic surgery, therefore, ventricular drainage surgery was also added. Her consciousness level did not recover and died on the 28th day. Aspergillus antibodies were confirmed from cerebrospinal fluid during treatment.

Pathological finding: Invasion of Aspergillus into the vessel wall of the BA was recognized. Destruction of elastic fiber, smooth muscle layers and outer membrane of the BA was confirmed, resulting in the rapid growth and rupture of the BA aneurysm.

Conclusion: It is a rare case of cerebral infarction and SAH caused by rupture of infectious aneurysm in Aspergillus.

P1‐23

Pathology of hypertensive cerebral hemorrhage: Revisiting miliary aneurysm of Charcot‐Bouchard using serial sections

Aya Takada^1,2; Kazuyuki Saito^1,2,3; Yoshie Hayashizaki^1,2; Hiroaki Nakanishi^1,3; Kumiko Asakura²; Satoko Kimura²

¹Department of Forensic Medicine, Saitama Medical University; ²Tokyo Medical Examiner's Office; ³Department of Forensic Medicine, Juntendo University Graduate School of Medicine

Introduction: It had been indicated that a hypertensive cerebral hemorrhage in the basal ganglia is accounted for by the rupture of microaneurysms of the small artery, referred to “miliary aneurysms (Charcot‐Bouchard)”. Nowadays, an abrupt rupture of penetrating branches of the lenticulostriate artery is thought to cause this condition, based on the atherosclerosis; however, this remains controversial. We pathologically examined culprit arterial lesions of hypertensive cerebral hemorrhages, and we present the pathology with persuasive photographic images.

Methods: We analyzed culprit lesions of the lenticulostriate arteries including “bleeding globes” in cerebral hemorrhages of the basal ganglia of five sudden death cases at our institutions, using serial sections.

Results: (1) The arteries ruptured abruptly, often at their bifurcations based on the atherosclerosis referred to as “lipohyalinosis,” which is often associated with arterial wall dissection. (2) Bleeding globes consisted of extravasation and fresh thrombi, without any previously formed aneurysmal wall. (3) There were often organizing or organized lesions of arterial ruptures in hemorrhagic and contralateral basal ganglia, occasionally with microinfarctions.

Conclusions: Hypertensive cerebral hemorrhage of the basal ganglion occurs as a result of an abrupt rupture of the lenticulostriate arteries based on atherosclerosis (“lipohyalinosis”). “Miliary aneurysm of Charcot‐Bouchard” and “angionecrosis” are organized or organizing features of an incomplete rupture of small arteries, and are not the cause of the cerebral hemorrhage.

P1‐24

Intracranial internal carotid artery injury as a rare cause of traumatic subarachnoid hemorrhage in non‐missile head injury: Clinicopathological analysis of nine forensic autopsy cases

Kazuyuki Saito^1,2,3; Aya Takada^2,3; Yoshie Hayashizaki^2,3; Naohito Kuroda⁴; Tetsuya Takagi^3,5; Hiroaki Nakanishi^1,2; Kumiko Asakura³; Satoko Kimura³

¹Department of Forensic Medicine, Juntendo University Graduate School of Medicine; ²Department of Forensic Medicine, Saitama Medical University; ³Tokyo Medical Examiner's Office; ⁴Department of Forensic Medicine, Fukushima Medical University; ⁵Department of Forensic Medicine, Tohoku Medical and Pharmaceutical University

Introduction: Intracranial internal carotid artery (IICA) injury is a rare cause of traumatic subarachnoid hemorrhage (SAH) due to non‐missile head trauma, and it has rarely been reported. We present nine forensic autopsy cases of IICA injury, and we discuss their clinicopathological characteristics.

Methods: We analyzed nine autopsy cases (all males, ages 20s‐70s) of IICA injury at our institutions.

Results: The circumstances of the sustained injuries were traffic accidents (n=5), fights (n=2), a fall from a tree, and a fall on a road. The head CT images were indistinguishable from those of a non‐traumatic SAH. Pathologically, the IICA injuries occurred before the bifurcation of the posterior communicating artery, showing a small laceration (less than several mm). Some arterial lacerations were covered with a fresh thrombus, making the lesions difficult to recognize macroscopically. The histological examination of the injured artery revealed an abrupt complete rupture, with a slight inward constriction of the internal and median layer. The adventitia extended outwards just a little. These morphological findings are quite different from those of a non‐traumatic aneurysm or dissection of an IICA. The lacerated areas were covered with an injury‐age‐dependent thrombus. In some cases, there was an organized disruption of the internal elastic lamina apart from the injured site.

Conclusion: In cases with a facial bruise, especially around the mandibular area, an IICA injury must be considered as a cause of a traumatic SAH. A detailed pathological evaluation is indispensable to distinguish traumatic from non‐traumatic SAHs.

P1‐25

“FAHR DISEASE” (symmetrical and selective cerebral calcification) is considered a kind of “ANGIOGENIC DISEASE” from the results of pathological and radiological studies

Eisuke Honda¹; Kiyoharu Inoue²; Kunio Ii³

¹Honda Occupational Health Consultant Office; ²Sapporo Yamanoue Hospital; ³Minami‐Awaji Hospital

Introduction: Fahr disease was named after Theodor Fahr who reported the autopsied case of cerebral calcification in 1930 and published the paper next year on the microscopic findings in the calcified cerebral microvessels.

Methods: 2 autopsied cases were studied with various methods such as histological examination, soft X‐ray roentgenography, contact microradiography(CMR), scanning electron microscopy (SEM), transmission electron microscopy(TEM).

Results: Calcifications were observed almost symmetrically and selectively in the predilection sites such as basal ganglia, dentate nucleus in the cerebellum, the floor of cerebral cortex. With CMR, the spindle‐shaped bodies of calcified entangled capillaries were found. With SEM, many calcified entangled capillaries were recognized on the surface of the brain stone. With TEM, electron dense psammoma‐like bodies were observed at the interface between the basement membrane and astrocyte in the cross section of the calcified capillary.

Discussion: From above results, we suppose that Ca and P extravasate through the endotherium of degenerated or damaged capillary wall probably due to the increased capillary permeability. This means that breakdown of blood brain barrier and accordingly neural system surrounded by capillaries lose its normal function secondarily both from insufficient supply of glucose & oxygen and from incompetent excretion of waste products. It is compatible with the clinical course that patients develop dementia gradually in proportion to severity of brain calcification.

Conclusion: FAHR DISEASE considered a kind of ANGIOGENIC DISEASE which affects both vascular system primarily and neural system secondarily in the long course of disease process.

P1‐26

Extensive calcifying CNS microangiopathy in a patient with scleroderma

Miren Aizpurua¹; Diana Marques Dias²; Claire Troakes²; Istvan Bodi^1,2

¹Clinical Neuropathology, Kings College Hospital NHS Foundation Trust, London, UK; ²MRC London Neurodegenerative Diseases Brain Bank. IOPPN, Kings College London, SGDP Centre, London, UK

Introduction: Systemic sclerosis and associated syndromes may induce primary vascular changes in the brain mimicking various neurodegenerative diseases. Although cerebral hypoperfusion has been found in half of the patients with a scleroderma diagnosis, neuropathological alterations are scarcely reported. Here, we describe a case of extensive calcifying CNS microangiopathy in a patient with scleroderma.

Clinical summary: We received a brain bank donation from a 59‐year‐old man initially diagnosed with CREST syndrome in his 30s. His neurological symptoms started 7 years ago and included progressive cognitive decline, tonic‐clonic epilepsy, parkinsonism, swallowing difficulties and postural hypotension. MMSE was 20/30 and brain MRI described subtle generalised increase in deep white matter signal of doubtful significance. There was no family history of dementia.

Pathological findings: Macroscopic examination revealed a moderately atrophic pons with mildly depigmented substantia nigra and locus coeruleus and mild cortical atrophy. Histology revealed prominent and widespread white matter pathology, also affecting the basis pontis. It consisted of multifocal, microinfarcts of varying duration associated with vascular abnormalities, such as vascular wall thickening, mineralisation, luminal obstruction and tortuosity. No other underlying cause for the vasculopathy or other neurodegenerative process was identified. The features were therefore in keeping with CNS microangiopathy secondary to scleroderma.

Conclusion: It has been suggested that scleroderma may induce primary vascular changes in the brain, of which calcification of small arteries and arterioles may be a marker. In our case the observed multifocal white matter microinfarcts were probably secondary to a microangiopathy crisis rarely described in scleroderma.

P1‐27

9‐year old girl with Cerebellopontine angle mass

Yuan Yuan¹; Qiuping Gui²

¹Department of Pathology, Beijing Tiantan Hospital; ²Department of Pathology, The PLA General Hospital

Introduction: Neuromuscular choristoma (NMC) is a benign lesion mostly occurred in cranial and spinal nerves. It is a rare lesion which composed of fascicular and nodular assembled muscle, connective tissue and nerve fibers. In most cases, neuromuscular choristomas have initially been misdiagnosed as vestibular schwannomas, which are the most common tumors at cerebellopontine angle.

Clinical summary: During surgery, a gray‐white, well‐demarcated mass was found at the left ponto‐cerebellar angle. The tumor appeared rubbery, had a rich vascular supply and did not firmly adhere to the trigeminal nerve. The patient experienced left facial paralysis after the operation. Follow up study showed postoperative recurrence twelve months later.

Pathological findings: Microscopically, the tumor predominantly consisted of strap‐shaped cells arranged in fascicular orientation, intermingled with mature nerve fibers. The tumor cells had frequent cross‐striations and peripherally located nuclei. Mitoses, atypia and necrosis were absent. Ki‐67 proliferation index was very low (3%). The tumor cells exhibited immunoreactive for Desmin, Vimentin, Myoglobin and CD56, patchy staining for S‐100, Actin (HHF35), CD34 and SMA. The tumor was negative for EMA and Myo‐D1.

Conclusion: NMC is fundamentally a benign lesion, but the risk of postoperative fibromatosis of this lesion is high. Resection is curative, although neurological deficits are a common consequence. No known characteristics in the clinical presentation or in imaging exist distinguishing these tumors from vestibular schwannomas. NMC should be included as a rare differential diagnosis in children patients with masses in the cerebellopontine angle.

P1‐28

The specific accumulation of subunit c of mitochondria ATP synthase and curvilinear profile in neuronal cytoplasm of methylenetetrahydrofolate reductase deficiency

Takahiro Fukuda¹; Masahito Hitosugi²; Tomohiro Kumada³; Eri Imagawa⁴; Noriko Miyake⁴; Naomichi Matsumoto⁴

¹Division of Neuropathology, Department of Pathology, The Jikei University School of Medicine; ²Div. of Legal Med., Shiga Univ. of Med. Sci.’; ³Dept. of Pediat., Shiga Med. Ctr. for Children.; ⁴Dept of Hum. Genet., Yokohama City Univ. Grad. Schl. of Med.

Introduction: Methylenetetrahydrofolate reductase deficiency (MTHFR) is the most common inborn error of folate metabolism. Two general types of pathologic finding often have been described. In the first, intimal hyperplasia and fragmentation, subintimal fibrosis, disruption of elastic lamellae, and thromboembolism are the results of homocystinemia. In the second, neuronal loss, decreased myelination, fibrillary astrogliosis, and reduction of oligodendroglia have been attributed to decreased availability of methyl groups. We report new pathological findings; subunit c of mitochondria ATP synthase (SCMAS) accumulation and curvilinear profile (CVP) in neuronal cytoplasm of cerebral cortex.

Clinical summary: The patient was 15‐year‐old female who originally had mental retardation (IQ 70 degree). She developed walking disturbance, psychomotor retardation, transient psychogenic blindness, tremor, and mental excitement. After she entered to hospital because of seizure during bathing, her seizure was unstable and body temperature rose to 39 degree Celsius. She suffered cardiopulmonary arrest caused by using thiopental sodium 2mg/kg for sedation during MRI. Resuscitation was carried out but she died. FLAIR images of MRI scan showed high intensity subcortical white matter lesions located at occipital lobes. Genetic study disclosed MTHFR (compound heterozygous mutation: c.446GC>TT and c.976G>A).

Pathological findings: Postmortem examination revealed subcortical perivascular demyelination with reactive astrocytosis and infiltration of macrophages in cerebrum with SCMAS accumulation and CVP in neuronal cytoplasm of cerebral cortex.

Conclusion: The specific accumulation of SCMAS has been reported in neuronal ceroid lipofuscinosis, and other lysosomal disorders. Also in MTHFR, SCMAS accumulated and might be related to form CVP.

P1‐29

Brain pathology of mucopolysaccharidosis type 2, mild form

Susumu Igarashi¹; Yukio Tsuura²; Toshiki Uchihara³; Takashi Irioka¹

¹Department of Neurology, Yokosuka Kyosai Hospital; ²Department of Diagnostic Pathology, Yokosuka Kyosai Hospital; ³Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, and Neuromorphomics laboratory, Nitobe‐memorial Nakano General Hospital

Introduction: Mucopolysaccharidosis type 2 (MPS2) is caused by insufficiency of iduronate‐2‐sulfatase enzyme, which results in accumulation of dermatan and heparan sulfates in tissues. Although brain pathology of severe MPS2 has been reported in detail, that of mild form is unknown. This is the first autopsy study of a patient with mild form of MPS2, who was treated with enzyme replacement therapy (ERT).

Clinical summary: A 42‐year‐old male was emergently hospitalized due to confusion and seizure. He was diagnosed as having MPS2 at 4 years‐old. He graduated from a junior college and could drive a car. The ERT was started at 41 years‐old but was stopped at 8 times because of gait difficulty. Brain MRI showed no ventriculomegaly but honeycomb signals in the bilateral basal ganglia and thalami. The patient died of ventricular fibrillation 2 months after the admission.

Pathological findings: The brain weighed 1595 g after fixation. There were many cavities in the subcortical white matter, basal ganglia and thalami. Neuronal loss and gliosis were present in the cerebral cortex and basal ganglia. The cerebral cortex was less injured. The remaining nerve cells did not show cytoplasmic ballooning. Perivascular spaces were dilated and filled with alcian blue and 10E4 (the antibody against heparan sulfate)‐positive material.

Conclusion: Our patient showed less neuronal loss and gliosis in the cerebral cortex than previously reported patients with severe MPS2. Ballooning neurons were less remarkable, and ventriculomegaly was absent. Brain pathology of MPS2 might be dependent on the clinical severity.

P1‐30

Typical Type I lissencephaly in Miller‐Dieker Syndrome: Report of an autopsy case.

Yoshinori Kodama¹; Taeko Saito²; Tatsuji Hasegawa³; Takeshi Yaoi¹; Kyoko Itoh¹

¹Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine; ²Department of Pediatrics, Kyoto Second Red Cross Hospital; ³Department of Pediatrics, Kyoto Prefectural University of Medicine

Introduction: Type I lissencephaly or Miller‐Dieker syndrome (MDS) is a rare disease, with a frequency of 1 per 100000 live births. MDS includes Type I lissencephaly and some other abnormalities. MDS is also known as a neuronal migration disorder, whose causative gene is LIS1 located in the short arm of chromosome 17 (17p13.3). An autopsied case with MDS is reported with a thorough review of English literatures.

Clinical summary: A female infant was delivered at 30 weeks of gestation by Caesarean section because of severe fetal growth restriction. She was diagnosed as MDS from the following findings: lissencepaly revealed by brain MRI, and other abnormalities such as small ventricular septal defect (VSD) and facial dysmorphology. Her chromosomal analysis showed a microdeletion on the 17p13.3. At two years old, she died of acute respiratory distress syndrome due to repeated pneumonia.

Pathological findings: Macroscopic findings showed facial abnormalities, including microcephaly, broad nasal bridge, an upturned nose, low set ears and prominent upper lip. The brain weighed 523 grams, showing complete agyria. Coronal section showed thickened cerebral cortex and thinned white matter, thinner corpus callosum, and enlarged ventricles. Microscopic examination showed a thick four‐layered cerebral cortex, composed of molecular layer, a thin superficial neuronal layer, a sparsely populated cellular layer and a thick neuronal layer. Heterotopia of inferior olivary nucleus was noted. The cerebellum was of normal structure.

Conclusion: We reported an autopsy case of MDS with histological, immunohistochemical and genetic examinations.

P1‐31

An autopsy case of late‐infantile GM1 gangliosidosis survived long duration with artificial respiratory support

Akiko Uchino^1,2; Makiko Nagai³; Kazutoshi Nishiyama³; Nobuyuki Yanagisawa⁴; Masaaki Ichinoe⁵; Kaori Adachi⁶; Eiji Nanba⁶; Hiroyuki Ishiura⁷; Kinuko Suzuki¹; Shigeo Murayama^1,8

¹Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Itabashi‐ku, Tokyo; ²Department of Neurology, Kitasato University Kitasato Institute Hospital, Minato‐ku, Tokyo; ³Department of Neurology, Kitasato University School of Medicine, Sagamihara‐shi, Kanagawa; ⁴Department of Pathology, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama‐shi, Kanagawa; ⁵Department of Pathology, Kitasato University School of Medicine, Sagamihara‐shi, Kanagawa; ⁶Research Center for Bioscience and Technology, Tottori University, Yonago‐shi, Tottori; ⁷Department of Neurology, Tokyo University School of Medicine, Bunkyo‐ku, Tokyo; ⁸Department of Neurology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Itabashi‐ku, Tokyo

Introduction: GM1 gangliosidosis is an autosomal recessive storage disorders caused by the deficiency of b‐galactosidase (GLB1), a lysosomal hydrolase. GM1 gangliosidosis is divided to three main clinical forms, infantile, late‐infantile and adult. We report an autopsy case of GM1 gangliosidosis who have received artificial respiratory support (ARS) and survived long duration.

Clinical summary: The patient was a 40‐year‐old woman, who was born after a normal pregnancy and delivery. She had difficulty in walking at the age of two and started having seizures at the age of nine. At the age of 21, she became bed‐ridden. At the age of 36, she had pneumoniae necessitating the introduction of ARS. She died of pneumoniae at age 40. Molecular study revealed c.152T>C (p.I51T), a common mutation for Japanese adult GM1 gangliosidosis, and c.1348‐2A>G mutations in GLB1. Autopsy was performed 3hour post mortem.

Results: The brain weighted 419g with severe atrophy predominantly observed in the frontal cortex. In the cerebral cortex and putamen, severe gliosis and loss of neurons were observed. A number of neurons of spinal cord, thalamus and hippocampal formation was relatively preserved. Severe neuronal swelling was seen in the amygdala, hippocampal formation, and the stored material in these neurons was negative with PAS. Neuronal cytoplasmic inclusions similar to membranous cytoplasmic bodies (MCB) were observed in the amygdala.

Conclusion: Clinical features and neuropathological findings were consistent with late‐infantile form although this patient had a common mutation for Japanese adult GM1 gangliosidosis. Despite of long duration, the limbic region was relatively preserved.

P1‐32

Chronic consequences of neonatal exposure to common organic solvents on behavior, motoric functions and brain morphology in young rats

Mirna Lechpammer¹; Krista A Thongphanh¹; Hilary A Gonzales¹; Taryn Morningstar¹; Joanne Y Chan¹; Veronica Martinez‐Cerdeno²; Evgeny Nudler³; David Zagzag⁴; Robert F Berman⁵

¹Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California Davis, Sacramento, CA, USA; ²Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA, USA; ³Howard Hughes Medical Institute and Department of Biochemistry, New York University School of Medicine, New York, NY, USA; ⁴Departments of Neurological Surgery, and Pathology, Division of Neuropathology, New York University School of Medicine, New York, NY, USA; ⁵Department of Neurological Surgery, and MIND Institute, University of California Davis, Sacramento, CA, USA

Introduction: Dimethyl sulfoxide (DMSO), propylene glycol (PG) and miglyol (MG) are common organic solvents often used to dissolve neuro‐pharmacological agents for in vivo assays in animal models of various pediatric brain disorders. Nonetheless, these compounds were reported to exhibit pharmacological and pathological effects on the central nervous system of their own. Here we report chronic effects of these solvents on behavior, motoric functions and brain morphology in young rats (P35‐37), following neonatal exposure to one of the compounds (P6).

Methods: Compounds were administered intraperitoneally (DMSO, 2 or 4 ml/kg; MG, 2 ml/kg) or per os (PG, 2.5 ml/kg) at concentrations considered safe and non‐interfering with neuroscience research. Age/sex matched controls received phosphate‐buffered saline (PBS). Animals were sacrificed following behavioral and locomotor assays (P40) and their brains were subjected to pathological analyses.

Results: Rats exposed to DMSO (n=10; 4 ml/kg only), spent significantly more time in the open field center and traveled shorter distance (p<0.05) vs. controls (n=10). Rats exposed to DMSO and MG exhibited shorter social interactions vs. controls (p<0.05). CatWalk gait analysis showed various disturbances (p<0.05) in rats exposed to any of the three compounds (DMSO, 4 ml/kg only). Brain pathological analyses revealed increased expression of microglia (Iba‐1+) and reactive astrocytes (GFAP+) in rats exposed to DMSO (p<0.05).

Conclusion: Observed chronic behavioral, motoric and morphologic sequelae of neonatal exposure to DMSO, PG or MG at concentrations that are generally considered safe raise concerns about under‐appreciated neuro‐toxicity of these common organic solvents, which warrants further exploration in larger translational studies.

P1‐33

Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in a pediatric patient: a case report

Shiho Yasue¹; Michio Ozeki¹; Saori Endo¹; Hirohito Yano²; Tomohiro Kanayama³; Natsuko Suzui³; Toru Iwama²; Tatsuhiko Miyazaki³; Toshiyuki Fukao¹

¹Department of Pediatrics, Graduate School of Medicine, Gifu University; ²Department of Neurosurgery, Graduate School of Medicine, Gifu University; ³Pathology Division, Gifu University Hospital

Introduction: Chordoma is a rare tumor (0.2% of brain tumors in children) involving the clivus and spine. Poorly differentiated chordoma is characterized by SMARCB1/INI1 deletion that is also seen in malignant rhabdoid tumors and atypical teratoma/rhabdoid tumors (AT/RTs). Therefore, for differential diagnosis between poorly differentiated chordoma and other diseases, pathological evaluation may be necessary for pediatric cases with a clivus lesion.

Clinical summary: A 2‐year‐old girl with an atrioventricular septal defect and pulmonary hypertension since birth had cervical pain for 2 months and left upper limb paralysis for 2 weeks. Magnetic resonance imaging (MRI) showed an extradural mass arising from the clivus, causing significant compression of the pons. Osteoblastic metastatic lesions were found in the left upper arm and right iliac bone. A tumor biopsy was performed through the oropharynx, which revealed an INI1‐negative small round cell tumor diagnosed as poorly differentiated chordoma. After four courses of combinatorial chemotherapy, a partial response was confirmed by MRI.

Pathological findings: Sections showed proliferation of small round cells and short spindle cells with distinct nucleoli and a high nuclear‐cytoplasmic ratio. Mitotic figures were occasionally seen (3/10 HPFs). Immunohistochemically, tumor cells were diffusely positive for AE1/AE3, vimentin, EMA, CD99, and Brachyury, but negative for LCA, S100P, desmin, synaptophysin, chromogranin A, NSE, myogenin, Myo D1, and CD1a. SMARCB1/INI1 immunoexpression was completely absent.

Conclusion: Combination of INI1 and Brachyury are useful to diagnose poorly differentiated chordoma.

P1‐34

Severe mental retardation associated to central nervous system developmental disorders. Report of two cases in Mexico (postmortem pathology)

Eduardo Navarrete Medina¹; JD Rembao Bojórquez²; C Salinas Lara²; ML Tena Suck²; J Sandoval Paredes²; A Camacho Molina²; L Becerril Cholula³; M Delgado Flores⁴; RA Franco Topete³; MA Tristán Agundis⁵

¹Hospital Civil de Guadalajara, “Dr. Juan I. Menchaca” UDG, México; ²Instituto Nacional de Neurología y Neurocirugía, México; ³Hospital Central Ignacio Morones Prieto UASLP, México; ⁴Facultad de Estudios Superiores Iztacala, México; ⁵Hospital Psiquiátrico Fray Bernardino Álvarez, México

Introduction: The World Health Organization defines mental retardation as the subnormal function of inteligente, originates during development and is associated with learning and social adaptation deficits.

Methods: Two autopsies were performed at the Fray Bernardino Álvarez psychiatric hospital for further analysis.

Clinical summary: #1: Woman, 31 years old, with severe mental retardation, poor comprehension and cognition from birth; responsive to verbal stimuli, emitted guttural sounds and few phone mes. She was admitted for postprandial emesis. During her hospitalization she presented respiratory symptoms, subsequently dying of respiratory failure.

#2: Male, 13 years old, with profound mental retardation. He made guttural sounds, had scattered attention. The electroencephalogram reported cortical neurons diffuse deficit. During his hospitalization presented undefined respiratory and enteral symptoms.

Results: #1: Microcephaly of 850 g, left cerebral hemisphere asymmetry and both temporal lobes hypoplasia. Microscopically, neuronal laminación loss, cortical dysplasia, heterotopias, globoid neurons, meganeurons with wavy axons; irregular fibers (length and thickness) massive fragmentation, arranged in whorls and decreased myelin. Cerebellum showed different size and thickness foliae, failed neuronal migration with hypoplasia.

#2: Microcephaly of 950 g, left cerebral hemisphere asymmetry, uncal hypoplasia, temporal lobes hypoplasia with focal lissencephaly, bilateral pachygyria in frontal and occipital lobes; loss of neuronal lamination, heterotopias, globular neurons, meganeurons with wavy axons, irregular fibers in length and thickness and some fragmented. The cerebellum development and neuronal migración alterations.

Conclusion: The nervous system development disorder was confirmed in both cases; with microcephaly, neuronal distortion, cortical dysplasia, failed neuronal migration, and severe alterations of myelination.

P1‐35

Clasmatodendrosis in Influenza‐Associated Encephalopathy is associated with dendritic spines and does not represent autophagic astrocyte death

M Tachibana^1,2; I Mohri^1,2; K Kagitani‐Shimono^1,2; H Fushimi³; T Inoue⁴; Y Kakuta⁵; S Murayama⁶; M Nakayama⁷; K Ozono²; M Taniike^1,2

¹Osaka University United Graduate School of Child Development; ²Department of Pediatrics, Osaka University Graduate School of Medicine; ³Department of Pathology, Osaka General Medical Center; ⁴Department of Pathology, Osaka City General Hospital; ⁵Department of Pathology, Japan Organization of Occupational Health and Safety, Yokohama Rosai Hospital; ⁶Division of Clinical Laboratory Medicine and Anatomic Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health; ⁷Tokyo Metropolitan Institute of Gerontology

Introduction: Influenza‐associated encephalopathy (IAE) is one of the most serious CNS complications of an influenza virus infection, with unclear pathophysiology. Clasmatodendrosis is a complex of morphological changes in astrocytes characterized by fragmentation of the distal processes and swollen cell bodies. Although pathologists in Japan have long been aware of the presence of clasmatodendrosis in IAE brains, few studies have been reported to date. We aimed to confirm the existence, and characterize the spatial distribution of clasmatodendrosis in postmortem IAE brains.

Methods: Autopsied brains from 7 patients with IAE and 8 non‐IAE subjects were examined immunohistochemically. In addition, immunofluorescent staining and electron microscopy were performed.

Results: Clasmatodendrosis was present in all examined regions of the IAE brains, but none of the control brains. Fragmented processes of astrocytes in IAE brains were closely adjacent to synapses on the dendritic spines, with the fragmentation especially prominent in the cerebellar molecular layer. In addition, the clasmatodendrotic astrocytes were negative for autophagy markers. Furthermore, whereas aquaporin 4 was predominantly detected in the perivascular endfeet of astrocytes in the control brains, its primary localization site shifted to the fragmented perisynaptic processes in the IAE brains.

Conclusion: Clasmatodendrosis was distributed diffusely in the IAE brains in close association with synapses, and was not caused by astrocyte autophagy. Clasmatodendrosis may be a suggestive pathological feature of IAE.

P1‐36

Classification systems in surgical pathology of drug resistant epilepsy: the old versus new

Rajalakshmi Poyuran^1,5; Anita Mahadevan¹; Arivazhagan Arimappamagan²; Mundlamuri Ravindranadh Chowdary³; Sanjib Sinha³; Rose Dawn Bharath⁴; Raghavendra Kenchaiah³; Jitender Saini⁴; Malla Bhaskara Rao²

¹Department of Neuropathology, NIMHANS, Bangalore, Karnataka, India; ²Department of Neurosurgery, NIMHANS, Bangalore, Karnataka, India; ³Department of Neurology, NIMHANS, Bangalore, Karnataka, India; ⁴Department of Neuroimaging and Interventional Radiology, NIMHANS, Bangalore, Karnataka, India; ⁵Department of Pathology, SCTIMST, Trivandrum, Kerala, India

Introduction: Drug resistant epilepsy (DRE) is a major cause of morbidity and about two‐thirds of DRE are amenable to surgery. Over four decades, several classifications have been introduced for the surgical pathology of DRE, particularly hippocampal sclerosis (HS) and focal cortical dysplasia (FCD). This study reviewed effect of ILAE classification on histopathological diagnosis.

Methods: 322 surgically treated DRE (2005‐2016) reviewed. For HS, Wyler grading and Blumcke classification were compared with ILAE 2013 classification. In FCD, Palmini classification was compared with ILAE 2011 classification.

Results: 88 cases (27.3%) underwent major revision with reallocation to a different diagnostic category. 5% were reclassified within the same category.

Of 30 mesial temporal sclerosis (MTS) diagnosed using Wyler grading system (2005‐2008), 92.3% of grade 4 and all grade 3 were classified as HS 1. Of 105 MTS diagnosed using Blumcke classification (2009‐2014), only 9.5% required resubtyping and the category of Probable HS was applied to nine.

Of 33 FCD (isolated‐10, associated‐23) as per Palmini classification system, 24 (72.7%) needed revision, 22 of which were FCD I and one each of FCD IIa and IIb. Although ILAE 2011 classification was used to characterize FCDs between 2011‐2016, interobserver discordance was noted in 64.9%, highest with FCD I (isolated‐50%, associated‐80%) and least with FCD IIb (6.3%).

Conclusion: With its more stringent criteria, ILAE classifications help define various pathologies more precisely. However, diagnosis of FCD I (isolated or associated) is still prone to high interobserver discordances and will await discovery of specific biomarkers.

P1‐37

A case of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE): a new pathological entity of frontal lobe epilepsy

Chenhui Mao¹; Wancheng Dou²; Qiang Lu¹; Liangrui Zhou³; Feng Feng⁴; Bin Peng¹; Ingmar Blumcke⁵; Yupu Guo¹

¹Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Science; ²Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science; ³Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science; ⁴Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science; ⁵Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany

Introduction: To analyze the clinical and histology characteristics of a patient with frontal lobe epilepsy diagnosed with mild malformation of cortical development with oligodendroglial hyperplasia, and to recognize the new neuropathological entity.

Clinical Summary: It was a female patient aged 16 y/o with 12 years history of epilepsy. The seizures manifested as episodes of conscious loss with automatism including grope and voice lasting for seconds. About 10 episodes a day were found and sometimes with secondary GTCS. MRI showed blurring of grey‐white matter interface in left orbital frontal cortex. VEEG revealed left frontal lobe origin of seizures. So left prefrontal lobe was removed.

Pathological findings: Histology showed almost normal of cortex neuropil and neurons. Blurring of grey‐white interface in some area with patches of proliferation of oligodendrocytes in the corresponding sub‐cortical white matter was found. The density of oligodendrocytes was significantly higher in sub‐cortical than deep white matter both shown in H&E and Oligo‐2 stain. Obvious oligodendrocytes increase and satellite phenomenon in deep cortical layer as well as increased ectopic neurons in sub‐cortical white matter was found in the lesion. In proliferation area, there were some nuclei stained with Ki‐67, but not as high as tumor. Subsequent follow up for 2 years proved the operation and benign prognosis.

Conclusion: There are special and undiscovered histopathological entities in epilepsy etiology. Although known as grey matter disease, white matter pathology plays an important role in epilepsy pathophysiology which will need further research.

P1‐38

Meningioangiomatosis: an incidental find during epilepsy surgery

Mihai Gheorghe Lisievici¹; Diana Pasov¹; Laurentiu Catalin Cocosila¹; Jan Ciurea²

¹Bagdasar‐Arseni Clinical Emergency Hospital, Department of Pathology; ²Bagdasar‐Arseni Clinical Emergency Hospital, Department of Neurosurgery SNC V

Introduction: Meningioangiomatosis is a rare malformative lesion usually affecting the leptomeninges and underlying cortex. Little over 120 cases have been reported yet incidence may be higher since clinical diagnosis alone may be very difficult.

Sporadic cases are usually solitary and manifest through epileptic seizures and headaches. Neurofibromatosis type II patients however may have multiple lesions and are asymptomatic.

Methods: A 32 years old male was diagnosed with drug resistant epilepsy at the age of 15. He presented two types of seizures of different intensity, both accompanied by headaches which severely affected his quality of life. Neuroimaging revealed an enlarged, edematous right temporal lobe which was interpreted as cortical dysplasia.

Neurosurgical resection of the affected region was decided.

Results: Grossly, the surgical specimen appeared unremarkable but was however thoroughly sectioned and embedded into paraffin blocks.

Microscopic evaluation of the resulted hematoxilin‐eosin slides revealed a thickening of the leptomeninges with meningothelial cells distributed intracortically, surrounding vascular structures throughout the cortical layer and sometimes adopting a more fibroblastic aspect. The lesion was accompanied by several psamomma bodies. A certain degree of cortical dysplasia was also observed but interpreted as reactive.

Conclusion: Out case represents the typical presentation of sporadic meningioangiomatosis. Despite the 17 years history of pharmacoresistant epilepsy, the diagnosis was not suspected before being confirmed by histopathological examination. Neurological improvement is to be expected but the case will require close follow‐up.

P1‐39

Eosinophilic astrocytic inclusions of the white matter in patient with epilepsy

Alaa Mohammad Alkhotani^1,2

¹Umm AlQura Univesity. Pathologyy Department; ²King Abdullah Medical City

Introduction: Glial and neuronal protein aggregations are known in neuropathological conditions such as neurodegenerative diseases, viral inclusions, low grade tumours and inclusions in clinical setting of epilepsy. Rarely, astrocytic inclusions are associated with seizure disorders but there are cortically located.

Clinical summary: This 39‐year‐old man has a long standing history of epilepsy. His imaging shows a focal right frontal cortical lesion. Cerebral biopsy is done.

Pathological findings: The histological examination shows small pieces of unoriented gray matter and white matter. The cerebral cortex shows focal neuronal clustering. Dysmorphic and balloon neurons are not seen. Numerous bright, eosinophilic astrocytic inclusions are seen throughout the white matter and they are located predominantly in the processes of the astrocytes. They are GFAP‐positive and they are negative for neurofilament, Alpha beta crystalin, PAS, Congo red, Alcian blue and Ziehl Neelsen. GFAP stain highlights gliosis in both grey and white matter. Neither neuronophagia nor well‐formed microglial nodules are identified. There is no evidence of malignancy. IDH‐1(R132H) is negative.

Conclusion: We report a case of unique astrocytic inclusions predominantly in the white matter in patient with long standing epilepsy. These inclusions are not similar to the previously reported inclusions in patient with epilepsy such as inclusions with filaminopathy. These inclusions could be the cause or the result of the long standing seizure. Further studies are needed to determine the exact nature of the inclusions for better understanding of the pathology.

P1‐40

Comprehensive analysis of protein expression profiles in sclerotic hippocampus from patients with mesial temporal lobe epilepsy

Ayako Furukawa¹; Akiyoshi Kakita²; Yoichi Chiba³; Shigeki Kameyama⁴; Atsuyoshi Shimada⁵

¹Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science; ²Brain Research Institute, Niigata University; ³Faculty of Medicine, Kagawa University; ⁴Dept. of Neurosurgery and Epilepsy Center, Nishi‐Niigata Chuo National Hospital; ⁵Faculty of Health Sciences, Kyorin University

Introduction: Hippocampal sclerosis (HS) is the most common neuropathological condition observed in adults with drug‐resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome. Many MTLE patients show HS, but some patients do not. The role of the sclerotic hippocampus in the causation and maintenance of MTLE has remained mostly unresolved. In order to elucidate the difference in protein expression profiles between hippocampal tissue of MTLE patients with and without HS, we performed 2‐Dimensional Fluorescence Difference Gel Electrophoresis (2D‐DIGE).

Methods: Surgically resected tissues of hippocampus and neocortex from drug‐resistant MTLE patients with (n = 10) or without HS (n = 10) were homoginized using lysis buffer (7 M urea, 2 M thiourea, 30mM Tris‐HCl, 4% CHAPS). Proteins were separated by 2D‐DIGE and identified by mass spectrometric amino acid sequencing.

Results: We identified 16 proteins at 18 spots in which the protein expression levels differed between sclerotic and non‐sclerotic hippocampi. Most of the identified proteins that underwent an increase or decrease in the expression level were known to be associated with synaptic loss due to neuronal death and gliosis. In addition, a decreased level of 3‐phosphoglycerate dehydrogenase (PHGDH), a protein expressed by astrocytes and an increased level of stathmin 1, a protein expressed by neurons were specific to sclerotic hippocampi.

Conclusion: Although the protein expression profile of HS was mostly expected from neuronal loss and gliosis, the decreased astrocytic PHGDH and increased neuronal stathmin 1 expression may represent pathognomonic changes of HS among MTLE patients.

Poster Session 1: P1‐41

Histopathological Findings in Brain Tissue of an anti‐NMDAR Encephalitis Patient Obtained during Epilepsy Surgery

Lei Liu¹; Yueshan Piao²; Jiawei Wang^1,3

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Pathology, Xuanwu Hospital, Capital Medical University; ³Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: An up‐to‐date multi‐centered research on neuropathology finding after epilepsy surgery suggested 1.5% patients were encephalitis. Autoimmune encephalitis is the recently recognized subtype of encephalitis during last decade and mainly mediated by autoantibodies. As the most common autoimmune encephalitis and only diagnosed by serology testing, neuropathological features of anti‐NMDAR encephalitis has been rarely described.

Methods: Case report.

Results: A 28‐year‐old man was presented for admission after 10 days of headache, nausea and episode of seizures. His past medical history was unremarkable and headache without fever had been attributed to non‐specific viral infection. MRI showed T2 FLAIR hyperintensity and focal gadolinium enhancement of the right temporal lobe. In MRS, choline peak was high, NAA peak was low and accompanied with lactate peak. His NAA/Cr ratio was 1.17 and Cho/Cr 2.67. An operation was performed for suspicious glioma. Histopathological examination revealed the lymphocytic infiltration of the leptomeninges and adjacent cortex, with scattered plasma cells and eosinophils. Perivascular lymphocytic cuffing, activated microglia, neuronal loss and degeneration were also noticed. But there was no necrosis, viral inclusions and microglial nodules, which may suggest infections. The inflammatory microscopic findings made autoimmune etiologies should be rule out. Later, autoimmune encephalitis antibody panels showed his serum and CSF were both anti‐NMDAR‐IgG positive. The diagnosis of anti‐NMDAR encephalitis was made.

Conclusions: Recent onset encephalitis without histological features of infection should raise the concern of autoimmune encephalitis. And the serology testing of specific autoantibodies may help to make the final diagnosis.

P1‐42

Pathological examination of transmantle sign of FCD exhibiting T1‐high‐intensity on magnetic resonance imaging

Ayako Shioya^1,2; Yukio Kimura³; Noriko Sato³; Naoki Ikegaya⁴; Masaki Iwasaki⁴; Masayuki Sasaki⁵; Akira Tamaoka⁶; Masahiro Sakamoto¹; Yuko Saito¹

¹Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry; ²Department of Neurology, Mito Kyodo General Hospital, University of Tsukuba; ³Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry; ⁴Department of Neurosurgery, National Center Hospital, National Center of Neurology and Psychiatry; ⁵Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry; ⁶Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba

Introduction: Transmantle sign is a characteristic radiological finding of FCD observed on magnetic resonance imaging (MRI). It generally exhibits high signal intensity on T2‐weighted and FLAIR images, and shows low signals on T1‐weighted images. However, in some cases, it showed high signal intensity on T1‐weighted images. Here, we examined the pathology in patients undergoing surgical resection in whom transmantle sign showed T1‐high signals.

Methods: There were 20 FCD patients who had transmantle sign on MRI. All of them underwent surgery for intractable epilepsy at our hospital. Patients were grouped based on T1‐intensity signal of the transmantle sign; high intensity, group H (n=8) and low intensity, group L (n=12)]. The pathological diagnosis was done according the ILAE classification. In addition, the density of the balloon cells was evaluated at a site where they could be observed in high number and the presence of the calcification was assessed in all cases.

Results: The age at surgery was 7.4± 5.9 and 26.7± 15.8 years in groups H and L, respectively. Based on pathological findings and ILAE classification, the diagnosis in all cases was FCD type IIb. Interestingly, the density of balloon cells tended to be higher in group H than in group L. Microcalcification was observed in 3 cases in group H, but was absent in group L.

Conclusion: The high density of balloon cells may contribute to the change in signal on MRI. Further studies are required to validate this information.

P1‐43

Epileptogenesis of the subiculum associated with hippocampal sclerosis in patients with MTLE

Hiroki Kitaura¹; Hiroshi Shirozu²; Hiroshi Masuda²; Masafumi Fukuda²; Yukihiko Fujii³; Akiyoshi Kakita¹

¹Dept.Pathology, Brain Res Inst., Niigata Univ.,; ²Dept.Neurosurgery, Nishi‐Niigata National Hosp.; ³Dept.Neurosurgery, Brain Res Inst., Niigata Univ.

Introduction: Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss as that referred to hippocampal sclerosis (HS). Accordingly, there is a paradox between the clinical and pathological features: why should epilepsy be derived from such degenerated tissue? Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE.

Methods: We prepared acute brain slices from patients with MTLE within 45 min after resection, and optical imaging or local field potential recordings (LFP) was performed ex vivo. We also used a brain block corresponding to the mirror surface of each slice and performed histopathological examination.

Results: We revealed that epileptiform activities developed from the subiculum, regardless of the existence of HS. We found spontaneous rhythmic activities in the subiculum and detected discrete component of high frequency oscillations (HFO), a clinical biomarker of the ECoG suggesting the epileptogenic regions. Immunohistochemistry of the HS tissue revealed loss of inwardly rectifying K+ channel 4.1 (Kir 4.1) in astrocytes in the subiculum, indicating failure of the extracellular K+ buffering and possible association with neuronal hyperexcitability.

Conclusion: These results indicate that pathophysiological alterations involving the subiculum could be responsible for epileptogenesis in patients with MTLE.

P1‐44

Reversible enlargment of amygdala without definite pathological abnormality

Rie Motoyama¹; Shigeo Murayama^1,2; Tomoyasu Matsubara²; Yasushi Nishina¹; Aya M. Tokumaru³; Mitsumoto Onaya⁴

¹Department of Neurology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Japan; ²Department of Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Japan; ³Department of Radiology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Japan; ⁴Department of Psychiatry, National Hospital Organization Shimofusa Psychiatric Medical Center

Introduction: Amygdala enlargement (AE) occurs in patients with temporal lobe epilepsy (TLE), however its underlying pathophysiology is unclear. Proposed pathology includes tumors, autoimmune mechanism and focal cortical dysplasia. Recent reports informed us that at follow‐up, 50% of TLE patients with AE became seizure‐free and 60% of them had partial or full remission of AE on brain MRI.

Clinical summary: A 66‐year‐old right‐ handed man visited the memory clinic of our hospital with chief complaint of memory skip. His Mini‐Mental State Examination score was normal (29/30) but CDR disclosed loss of distant memory with well preserved recent memory. Brain MRI showed enlargement of the left amygdala but EEG could not detect abnormality. Therapeutic trial of zonisamide 100mg per day completely ameliorated symptoms. From 68 years of age, zonisamide was tapered down to zero for three years. At age 73, a follow‐ up MRI showed full remission of initial AE. Just after the MRI, he died unexpectedly at home.

Pathological findings: No definite pathological findings were present in his central nervous system, including amygdala.

Conclusion: This case may indicate that the reversible AE with TLE may require different approach to prove it pathogenesis. The cause of death may be classified into unexpected death of epilepsy, warning cession of anti‐ epileptic drugs even without clinical symptoms of this syndrome.

P1‐45

Hippocampal morphometry in sudden and unexpected death in epilepsy (SUDEP)

Maria Thom; Alyma Somani; Anita‐Beatric Zborovschi; Yan Liu; Smriti Patodia; Zuzanna Michalak; Sanjay Sisodiya

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology

Introduction: Hippocampal developmental abnormalities, including granule cell dispersion (GCD) of the dentate gyrus (DG), DG invaginations (DGI) and subiculum/hippocampal malrotation (SM) have been reported in sudden unexpected death in childhood, and proposed as risk biomarkers. GCD is a common finding in temporal lobe epilepsy with hippocampal sclerosis (HS). Our aim was to investigate morphological hippocampal alterations in SUDEP.

Methods: In 186 post‐mortems from three groups [SUDEP (67; 13 with HS), non‐SUDEP epilepsy controls (EC =66; 23 with HS) and non‐epilepsy controls (NEC= 53)] Nissl/H&E stained sections from left and right hippocampus at several coronal levels were digitised. Image analysis for mean GCD (inner and outer DG), DGI, SM and hippocampal dimensions (HD) for shape [width (HD1), height (HD2)] and medial positioning [(HD4) in relation to parahippocampal gyrus (PHG) length (HD3)] were measured, with multivariate statistical comparisons between groups.

Results: Findings included significant GCD in all cases with HS than those without (p<0.001). In non‐HS cases a trend for increased GCD in EC compared to NEC (p<0.05) but not between SUDEP and NEC was noted. There was no significant difference in the presence of DGI, SM, HD1 and HD2 lengths between SUDEP, EC and NEC groups, when factoring for HS and coronal level. HD3 was significantly greater in SUDEP than NEC and EC (p<0.01) when factoring for presence of HS and coronal level; however multivariate analysis considering age at death showed no significant differences in HD3 between the three groups.

Conclusions: No signature histological hippocampal morphometric alterations were identified in SUDEP.

P1‐46

Focal cortical dysplasia associated with CNS injury in early childhood

Mrinalini Honavar¹; Istvan Bodi²; Richard Selway³; Charles E Polkey³

¹Department of Anatomic Pathology, Hospital Pedro Hispano, Matosinhos, Portugal; ²Department of Clinical Neuropathology, King's College Hospital, London, UK; ³Department of Neurosurgery, King's College Hospital, London, UK

Introduction: Intrauterine or perinatal hypoxic‐ischemic injury causes encephaloclastic lesions associated with morphological alterations of focal cortical dysplasia (FCD) in the better preserved cortex. To determine if FCD occurred following injury later in infancy or childhood, we examined surgical resection specimens from patients being treated for intractable epilepsy with a history of an injurious event in early life, beyond the perinatal period.

Methods: Twelve cases, from the archives of the Department of Clinical Neuropathology, Kings College Hospital, London, were reviewed.

Results: Patients ranged from 8 to 39 years at surgery, with seizure onset from 1 month to 8 years. The precipitating events were infections, head injury due to falls and shaking, neonatal hypoglycemia and cerebrovascular accident related to congenital heart malformation, occurring mostly within the neonatal period to the first year of life. Principal lesions were porencephaly in the multilobar resections and ulegyria; in three, marbled cortex was seen. Adjacent cortex showed nodules and clusters of neurons, which were frequently hypertrophic. In four specimens, there was thin unlayered cortex, in two, microcolumnar arrangement of neurons and scattered dysmorphic neurons in two.

Conclusion: Changes of FCD do result from disturbed postnatal development and reorganization of less damaged cortex, and may be responsible for the epilepsy.

P1‐47

Male of 19 years with superefractory genetic epilepsy associated to bilateral porencephaly. Case report in Mexico

E Navarrete Medina¹; JD Rembao Bojórquez²; C Salinas Lara²; ML Tena Suck²; J Sandoval Paredes²; A Camacho Molina²; L Becerril Cholula³; M Delgado Flores⁴; RA Franco Topete³; MA Tristán Agundis⁵

¹Hospital Civil Juan I. Menchaca UDG, México; ²Instituto Nacional de Neurología y Neurocirugía, México; ³Hospital Central Ignacio Morones Prieto UASLP, México; ⁴Facultad de Estudios Superiores Iztacala, México; ⁵Hospital Psiquiátrico Fray Bernardino Álvarez, México

Introduction: Some epileptic seizures come from punctual genetic defects, which can be confirmed by established molecular tests, or genetic component evidence derived from familiar and genetic studies.

Methods: Autopsy was performed at the Fray Bernardino Álvarez psychiatric hospital for further anatomopathologic and molecular analysis.

Clinical summary: A 19‐year‐old male presents epilepsy since childhood. Family history of consanguinity (grandparents, parents), brother with epilepsy and carrier of mutation in a heterozygous state composed of TBC1D24 gene, CPA6 (c.799G> A, P. Gly267Arg and c.619C> G, P. Gln207Glu). Product of full‐term pregnancy, eutocic delivery, birth weight 3060 g. Emited first word at 24 months. At 3 years old he presented absence crisis, behavior arrest and abnormal crying. At 16 years with episodes of dystonia, blinking, right upper limb clonic seizures, secondarily generalized. Treatment with regular crisis control. In 2016, associated with a reduction in CBZ, he presented mood alterations, clonic movements in the right hand, progressing to hemibody, lasting 1 hour. He presented multiple generalized clonic tonic crises (up to 40 daily), with an average duration of 5 minutes, returning partially to baseline.

Results: Autopsy findings: brain weighed 1250 g, with left cerebral hemisphere asymmetry, extensive frontal lobe lissencephaly, incomplete corpus callosum, extensive ventricular and cisternal communication, and two porencephalic cysts at the middle brain, resembling accessory ventricles, both had internal choroid plexuses, identified as extensions from the lateral ventricles.

Conclusion: This case showcases the relationship between familial epilepsy, TBC1D24 mutations and bilateral porencephaly.

P1‐48

Pathological characteristics of peripheral neuropathy in eosinophilic granulomatosis with polyangitis

Ryota Sato; Masatoshi Omoto; Yukio Takeshita; Takashi Kanda

Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder, defined pathologically as the combination of extravascular granulomas, small and medium‐sized vessel vasculitis and the eosinophilic infiltrates. Anti‐neutrophil cytoplasmic antibody (ANCA) have been demonstrated in 30‐40% of EGPA patients. We have the hypothesis that pathogenic mechanism of neuropathy in EGPA is distinct between ANCA‐positive and negative patients.

Method: We retrospectively examined histological features of sural nerve biopsy specimen in 16 EGPA patients (4 ANCA‐positive and 12 ANCA‐negative).

Results: Necrotizing vasculitis were shown in 25% (1/4) of ANCA‐positive patients and in 8% (1/12) of ANCA ‐negative patients. Ischemic pattern of axon loss was shown in 50% (2/4) of the ANCA‐positive patients and in 17% (2/12) of ANCA ‐negative patients. Eosinophilic infiltrations in the epineurium and degranulations of eosinophilias were shown in 33% (4/12) of ANCA‐negative patients, while no ANCA‐positive patients showed these changes.

Conclusion: There were two pathogenesis in EGPA with neuropathy, ischemia with vasculitis and toxic eosinophilic effect. Necrotizing vasculitis and ischemic pattern of axon loss were observed more frequently in ANCA‐positive EGPA patients than in ANCA‐negative patients. Eosinophilic infiltrations in the epineurium and degranulations of eosinophiles were found only in ANCA‐negative patients. These findings suggest that, in ANCA‐negative EGPA patients, a toxic effect on nerve fibers associated with eosinophilic infiltrations is the cardinal feature to cause peripheral neuropathy, not vasculitic occlusion due to small vessel vasculitis.

P1‐49

Label‐free visualization of abnormal lipid accumulation in tissues from Fabry disease patients using Raman spectroscopic marker of globotriaosylceramide

Yu Nagashima^1,2; Atsushi Iwata¹; Kosuke Yoshioka³; Junko Omachi²; Jun Shimizu¹; Tatsushi Toda¹; Junji Yumoto¹; Makoto Kuwata Gonokami²

¹School of Medicine, The University of Tokyo; ²School of Science, The University of Tokyo; ³School of Engineering, The University of Tokyo

Introduction: Fabry disease is a genetic disorder resulting from deficient activity of alpha‐galactosidase A. It causes systemic accumulation of globotriaoslyceramide (Gb3) in plasma and cellular lysosomes of tissues throughout the body. In routine histopathological studies, toluidine blue staining usually demonstrates Gb3 accumulation, but it is not molecular specific and the other lipids are potentially stained at the same time. In this study, we measured molecular vibrational spectra of Gb3 using Raman spectroscopy. They provide vibrational information characteristic of chemical groups or bonds in a molecule without any labeling procedures. Tracing spectral fingerprints enables us to locate and quantitate Gb3 within tissues in a molecular specific manner.

Methods: Vibrational spectra of a 10µm‐thick frozen sections of peripheral nerves biopsied or autopsied from three Fabry disease patients were obtained using spontaneous Raman microspectroscopy and compared with the spectra of Gb3, phosphatidylcholine (PC) and sphingomyelin (SM) in vitro.

Results: The Raman shift in 1064cm^‐1 was more prominent in PC and SM than in Gb3, whereas the Raman shift in 1088cm^‐1 only existed in Gb3. The ratio of them (1088cm^‐1 to 1064cm^‐1) enabled us to visualize Gb3 in the perineurium around PC‐ and SM‐rich nerve fibers in Fabry disease patients. This ratio was not elevated in the sections from the disease control (vasculitis) cases.

Conclusions: The Raman shifts worked as a molecular specific marker of Gb3 within the tissues from the patients. This is a label‐free and lipid‐specific visualization technique of Gb3 and is potentially useful even within the tissues other than peripheral nerves.

P1‐50

Vasculopathy in hereditary transthyretin amyloidosis: an electron microscopic study

Haruki Koike¹; Ryoji Nishi¹; Shohei Ikeda¹; Yuichi Kawagashira¹; Masahiro Iijima¹; Yohei Misumi²; Yukio Ando²; Shu‐ichi Ikeda³; Masahisa Katsuno¹; Gen Sobue¹

¹Nagoya University Graduate School of Medicine; ²Kumamoto University; ³Shinshu University Hospital

Introduction: Peripheral neuropathy is the cardinal feature of hereditary transthyretin (ATTRm) amyloidosis, but its mechanism has not been fully elucidated.

Methods: We used electron microscopy to examine sural nerve biopsy specimens from 49 ATTRm amyloidosis patients with Val30Met mutation. Patients were consisted of 11 early onset cases from endemic foci and 38 late onset cases from non‐endemic areas.

Results: Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early onset cases than in late onset cases. The atrophy of Schwann cells, particularly nonmyelinating cells, that were apposed to amyloid fibrils was more conspicuous in early onset cases than in late onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the ATTRm amyloidosis patients compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood‐nerve barriers, such as the loss of tight junctions and the fenestration of endothelial cells, were also more frequently found in the ATTRm amyloidosis patients (p < 0.001), irrespective of the presence or absence of amyloid deposition.

Conclusions: These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage resulting in the predominant loss of small‐fiber axons characteristic of early onset cases. In addition, vasculopathy may also participate in the pathogenesis of neuropathy, particularly in late onset cases.

P1‐51

An autopsy case of acute autonomic and sensory neuropathy

Hiroto Nakano¹; Kenji Sakai¹; Ai Shimizu¹; Tsuyoshi Hamaguchi¹; Oi Akishi²; Masahito Yamada¹

¹Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences; ²Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Sciences

Introduction: Patients with acute autonomic and sensory neuropathy (AASN) often present with psychosis; however, the pathomechanisms underlying the psychiatric symptoms have remained unclear so far.

Clinical summary: A 46‐year‐old man developed spontaneous pain of his trunk and four limbs with stomach ache. Neurological examination revealed character changes, mydriasis, and impairment of superficial sensations with spontaneous pain over the entire body. Deep sensation was normal in his four limbs. The autonomic dysfunctions including orthostatic hypotension, bladder and bowel dysfunction, and hypohidrosis were shown. Mild muscle weakness was observed in his four limbs. Nerve conduction studies revealed sensory‐dominant axonal neuropathy. Cervical MRI demonstrated hyperintense lesions on the T2‐weighted images in the dorsal area of the spinal cord at the C3‐7 vertebral levels. Sural nerve biopsy revealed severe loss of the myelinated fibers (2,462/mm²).

Pathological findings: The cerebrum showed mild atrophy of the bilateral frontal lobes. On histopathologic examination, no abnormalities were demonstrated in the cerebrum, cerebellum, or brain stem. In the dorsal column of the spinal cord, severe loss of the myelinated fibers with infiltration of macrophages and perivascular lymphocytes comprising of CD8‐positive T lymphocytes was observed. The number of the myelinated fibers in the dorsal roots were severely decreased; however, the anterior roots were preserved. Obvious loss of the ganglion cells with formation of the Nageotte's nodules in the sympathetic and dorsal root ganglia were seen. The intermediolateral nucleus of the thoracic cord was intact.

Conclusion: The pathological changes responsible for the character changes in our patient could not be detected.

P1‐52

Peripheral polyneuropathy associated with leptomeningeal carcinomatosis and lymphomatosis: diseases simulating Guillain Barre syndrome. Report of two postmortem cases

Eric Eduardo Mendoza; Erick Apo; Reyna Lopez; Janeet Garduno; Valentin Gonzalez; Mariana Torres; Laura Chavez

Department of neuropathology, General Hospital of Mexico Dr. Eduardo Liceaga

Introduction: Lymphomatosis and leptomeningeal carcinomatosis are a dissemination through the subarachnoid space, affecting cranial nerves, medullary roots and/or cerebral and medullary parenchyma. It is subacute, with headache and deficit of the cranial and spinal nerves.

Clinical summary: Case 1: a 51 year old woman with pain in the right hypochondrium who returned with treatment in 2015, later diplopia and paresis of the pelvic limbs, remaining bedridden with a diminished tone and reflexes of absent muscle stretching and diagnosis of Guillain‐Barre syndrome, later she died. Case 2: a 58 year old man with a diagnosis of chronic polyneuropathy in 2015 managed with immunoglobulin therapy without improvement. In 2016 he showed prostate enlargement by ultrasound. Later, he presented an infection in the left pelvic limb and a torpid evolution with absence of vital signs, declaring his death.

Pathological findings: Case1: adenocarcinoma of the gallbladder, with extension to the liver bed and metastasis to multiple organs. The histology shows neoplastic cells in the subarachnoid space, wrapping the anterior medullary roots and conditioning central chromatolysis of the motor neurons. Case 2: enlarged prostate, whitish and solid. The histology shows diffuse infiltration by small cells with hyperchromatic nuclei, increased nucleus‐cytoplasm ratio and involvement of multiple organs. Positive immunohistochemistry for CD20, bcl‐2 and CD10, diagnosed as grade I diffuse follicular lymphoma.

Conclusion: Because treatment in Guillain Barre syndrome is more effective when administered earlier, patients should be treated after the exclusion of possible imitators such as leptomeningeal dissemination due to neoplasm.

P1‐53

B cell activating factor (BAFF) expression in active phase of vasculitic neuropathies

Teruaki Kawasaki^1,3; Nobuyuki Oka²; Hiroki Takeuchi²; Kazuo Shigematsu²; Hideo Yagi³; Ichiro Akiguchi^1,3

¹Kyoto Clinical and Translational Research Center for Neurocognitive Disorders; ²National Hospital Organization Minami‐Kyoto Hospital, Department of Neurology; ³Koseikai Takeda Hospital, Center of Neurological and Cerebrovascular Diseases

Introduction: Various factors including proinflammatory cytokines which affect humoral and cellular immunity, have been related to the onset of vasculitic neuropathies. Recently, the presence of ectopic B cell follicular‐like structures has been reported in many autoimmune disorders and the importance of B cell in the pathogenesis of immune mediated neurologic disorders. BAFF recently has been identified as one key molecule in the pathogenesis of autoimmune disorders and regulates B cell proliferation and survival. To clarify the role of BAFF in peripheral nerve with vascular inflammation, we examined the expression of BAFF and its receptor using immunohistochemistry.

Material and Methods: Sural nerve biopsy specimens from patients with RA (n=5), MPA (n=5), EGPA (n=5) were studied by immunohistochemistry. Each patient provided informed consent. Consecutive paraffin sections were each immunostained with primary antibodies (antiBAFF, antiBAFF‐R, CD3, CD20, CD68).

Results: In 11 of 15 cases, BAFF immunoreactivity showed at perivascular infiltrates in the epineurium. Most of them were CD68 positive macrophages. In cases of highly expression of T cell, BAFF expression seems to be scarce. In the active phase of vasculitis with accumulation of B lymphocytes, perivascular infiltrates showed highly immunoreactivity for BAFF.

Conclusion: BAFF immunoreactivity for the active phase of vasculitic neuropathies was identified at perivascular infiltrates in epineurium. It may reflect a breakdown of B cell tolerance and an increase in autoantibody production due to autoreactive B cell induced by a BAFF stimulation.

P1‐54

Anti‐HMGCR antibody shows bcl‐2‐positive lymphocyte infiltration and follicles

Takashi Kurashige¹; Tomomi Kanbara^1,2; Naoko Sumi¹; Tomohito Sugiura¹; Hirofumi Maruyama³; Tsuyoshi Torii¹

¹Department of Neurology, NHO Kure Medical Center / Chugoku Cancer Center; ²Department of Neurology, NHO Hiroshima‐nishi Medical Center; ³Department of Clinical Neuroscience and Therapeutics, Hiroshima Univiersity Graduate School of Biomedical and Health Sciences

Introduction: Idiopathic inflammatory myopathies (IIM) are classified in five categories including polymyositis (PM), dermatomyositis (DM), immune‐mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), and non‐specific myositis by their muscle pathologies findings. In addition, more than 15 autoantibodies specific for myositis including anti‐HMGCoA reductase (HMGCR) antibody are already recognized. HMGCR affects the supression of low grade lymphoma by regulating mevalonate pathway. In this study, we aimed to determine the association between anti‐HMGCR antibody positive IMNM and a specific morphological phenotype.

Materials and methods: We studied patients with anti‐HMGCR antibody positive IMNM (n=10), other IMNM (n=20), PM (n=12), DM (n=12), and IBM (n=14). Their muscle biopsy specimens were subjected to routine histochemistry and immunohistochemistry.

Results: In anti‐HMGCR antibody positive patients, perivascular bcl‐2 positive lymphocyte infiltrations were frequently observed. About 50% of all inflammatory cells were positive for bcl‐2. In addition, extranodal lymphocytic follicles are scatterd in cases with anti‐HMGCR antibody and higher serum LDL‐cholesterol levels. In these follicles, lymophcytes were positive for bcl‐2, CD4, CD8, and CD79a, but not for CD20. Abnormal lymphocytes were not observed in all cases. In IIM except for anti‐HMGCR antibody positive IMNM, bcl‐2 positive lymphocytes were less than 5% of all inflammatory cells. Ki‐67 positive lymphocytes were less than 5% of inflammatory cells in all cases.

Conclusion: Our data showed that bcl‐2‐positive lymphocyte infiltration are specific for anti‐HMGCR antibody positive myopathy. These findings suggested that effects of anti‐HMGCR antibody might be contrary to those of statins.

P1‐55

Fatal disseminated Annacaliia algerae myositis mimicking polymyositis in an immunocompromised patient

Fouzia Ziad¹; Thomas Robertson²; Damien Stark³; Matthew Watts⁴; Linda Graham⁵; Clinton Turner⁶; Justin Copeland⁷; Graham Chiu⁸; Richard Newbury⁹; Michael Addidle¹⁰

¹Dept of Pathology,Waikato Hospital,Hamilton; ²Pathology Queensland, Royal Brisbane and Womens Hospital, Australia; ³St Vincents Hospital, Darlinghurst, New South Wales, Australia; ⁴Centre for Infectious Diseases and Microbiology Public Health, Westmead, New South Wales, Australia; ⁵Anatomical Pathology, LabPlus, Auckland City Hospital, New Zealand; ⁶Anatomical Pathology, LabPlus, Auckland City Hospital, New Zealand; ⁷Pathlab Bay of Plenty, New Zealand; ⁸QE Health, Rotorua, New Zealand; ⁹Lakes District Health Board, Rotorua, New Zealand; ¹⁰Pathlab Bay of Plenty, New Zealand

Introduction: Anncaliia algerae myositis is a rare, life‐threatening, microsporidiosis among immunocompromised hosts which can be potentially cured if treatment is instituted prior to clinical deterioration. We report a case of A algerae myositis in a man who was on long term immunosuppression for treatment of psoriatic arthritis.

Clinical summary: A 55 year old man with a long history of treatment with immunosuppressive agents including methotrexate, leflunomide and corticosteroids for psoriatic arthropathy was investigated for an unexplained myositis. A vastus lateralis muscle biopsy performed led to a diagnosis of A. algerae microsporidial myositis. Immunosuppressive drugs were stopped and patient was treated with cholestyramine wash and albendazole. He also developed Pneumocystis jirovecii pneumonia which was treated with IV. Despite therapy, patient deteriorated with involvement of bulbar and respiratory muscles requiring intensive care and ventilation. He died 3 weeks after diagnosis.

Pathological findings: Light microscopy demonstrated a necrotizing myositis with scattered clusters of ovoid spores within the myocyte cytoplasm resembling microsporidia. DNA was extracted from the muscle biopsy specimen, amplified by PCR and subsequent sequence analysis was consistent with A. algerae. Electron microscopy confirmed microsporidial myositis with features characteristic of A. algerae. Post mortem examination of skeletal muscle from tongue and intercostal muscles also revealed numerous organisms confirming disseminated disease.

Conclusion: A high index of suspicion is required for the diagnosis of this rare, but often fatal microsporidial myositis in immunocompromised patients. A timely muscle biopsy can lead to diagnosis and directed therapy.

P1‐56

Pathological finding of the first autopsy case with adenylosuccinate synthetase‐like 1 (ADSSL1) gene mutation myopathy

Atsuko Motoda^1,3; Chigusa Watanabe¹; Masahiro Higaki¹; Takako Makino¹; Yoshiro Tachiyama²; Kazuhide Ochi³; Tetsuya Takahashi³; Ichizo Nishino⁴; Hirofumi Maruyama³

¹Department of Neurology, Hiroshima‐nishi Medical Center; ²Department of Pathology, Hiroshima‐nishi Medical Center; ³Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Institute of Biomedical and Health Sciences; ⁴National Center of Neurology and Psychiatry, Department of Neuromuscular Research

Introduction: ADSSL1 myopathy is one of the myopathy inherited in an autosomal recessive fashion. ADSSL1 gene is also known as one of the beta‐amyloid(Aβ) toxicity modifier genes. We report a 66‐year‐old man with ADSSL1 myopathy in the course of 30 years, the first autopsy case.

Clinical summary: He could not run well since student. He had no family history of neuromuscular disease. In the late thirties, he could not step stairs with his own feet. At the age of 56, he could not walk without support. Next year, he admitted to the hospital with dyspnea, diagnosed Brugada syndrome and implanted a cardioverter defibrillator. At the same time, he referred to the neurology division and presented dysphagia and muscle weakness in face, respiratory muscles and distal limbs. Cognitive function was normal. Serum creatine kinase was 45 mU/ml. Electromyography showed myogenic change. At the age of 66, He died of respiratory failure seven months after tracheotomy. Genetic examination revealed heterozygous c.910G>A ADSSL1 gene mutation.

Pathological findings: Muscle necropsy showed chronic myopathic features with a few nemaline rods, some rimmed vacuoles and type 1 fiber predominance. Fixed brain weighed 1460g. Senile plaque Braak stage A, Neurofibrillary tangle Braak stage 2. Alpha synuclein and TDP‐43 were negative. The spinal cord was unremarkable.

Conclusion: Muscle pathology findings were similar to the past reports, suggesting the specific findings with ADSSL1 gene mutation. Mild Aβ deposition was found in the brain, but further investigation is needed to clarify the relation to ADSSL1 gene mutation.

P1‐57

Clinical and pathological features in patients with Nakajo‐Nishimura syndrome and inclusion body myositis

Megumi Mori¹; Nobuo Kanazawa²; Kayo Kunimoto²; Kenya Murata^1,3; Hidehumi Ito¹

¹Department of Neurology, Wakayama Medical University; ²Department of Dermatology, Wakayama Medical University; ³Center for Educational Research and Development, Wakayama Medical University

Introduction: Nakajo‐Nishimura syndrome (NNS) is an autosomal recessive disease characterized by remittent fever, skin rash, emaciation of the face and upper body, and long gnarled fingers with contractures. Mutation of the gene encoding the β5i subunit of the immunoproteasome causes the accumulation of ubiquitinated or oxidated protein due to proteasomal dysfunction. Inclusion body myositis (IBM) is a form of inflammatory myositis characterized by weakness and atrophy of the quadriceps femoris (QF) and flexor digitorum profundus (FDP). Although the pathogenesis of IBM is unknown, inflammation, degeneration, proteasomal dysfunction are thought to be its underlying mechanisms. In this study, we investigated the clinical and pathological features of NNS and IBM.

Methods: We examined the clinical symptoms (e.g., region of weakness, muscle magnetic resonance imaging (MRI), and laboratory data) of 4 NNS patients. Immunohistological studies of muscle biopsy specimens from NNS and IBM patients were also performed.

Results: Weakness of the QF and FDP and high‐signal intensity in T2WI were observed in IBM and NNS patients. One NNS patient with dysphagia had impaired relaxation of the cricopharyngeal muscle, which was also characteristic of IBM patients. We found p62‐positive cytoplasmic deposits and Lys63‐ and Ly48‐linked polyubiquitin‐positive deposits in muscle specimens from NNS and IBM patients.

Conclusion: NNS and IBM patients share many common clinical findings. Furthermore, both groups of patients have similar pathological findings, which involve the ubiquitin‐proteasome system and selective autophagy. Our study suggests that dysfunction of these pathways plays an important role in the pathogenesis of both diseases.

P1‐58

Myopathological features of cancer‐free myositis with anti‐TIF1‐γ‐Ab positive

Kenichiro Taira¹; Naohiro Uchio¹; Atsushi Unuma¹; Masato Kadoya²; Chiseko Ikenaga¹; Akatsuki Kubota¹; Jun Shimizu¹; Tatsushi Toda¹

¹Department of Neurology, Graduate School of Medicine, The University of Tokyo; ²Department of Neurology and Anti‐aging Medicine, National Defense Medical College

Objective: Cancer is not detected in juvenile myositis patients with anti‐transcriptional intermediary factor 1 γ autoantibody (anti‐TIF1‐γ‐Ab), but is common in those adult patients. We aimed to characterize myopathological features associated with anti‐TIF1‐γ‐Ab itself by excluding the background of cancer‐associated myositis (CAM).

Methods: We reviewed the database of 945 adult patients with idiopathic inflammatory myopathies between May 2000 and November 2017. Anti‐TIF1‐γ‐Ab was analyzed by immunoprecipitation assays. Among anti‐TIF1‐γ‐Ab(+) patients, the cancer‐free patients, who were not detected cancer over three years after myositis diagnosis and did not include cancer history, were compared with those with CAM who had cancer within three years of myositis onset.

Results: A total of 80 patients with anti‐TIF1‐γ‐Ab(+) were included (DM 77). Among them, in comparison to 57 with CAM, 13 cancer‐free patients were identified with long‐term follow‐up (6.0 ± 2.4 years, range 3.0 to 10.5 years from myositis onset). Those patients were not younger (58.9 ± 19.0 years) with longer duration (8.0 ± 10.3 months, p < 0.05), and showed lower serum CK levels (349 ± 339 IU/L, p < 0.05). In myopathology, vacuolated fibers were less frequent (31% vs 61%, p < 0.05), but perifascicular atrophy (38% vs 35%) and C5b‐9 deposits on capillaries (46% vs 67%) were in a similar proportion.

Conclusion: The CAM can induce vasculopathy of vacuolated fibers with higher CK levels. Myopathological findings of cancer‐free myositis patients with anti‐TIF1‐γ‐Ab(+) are associated with PFA or C5b‐9 deposits. Our findings can give a new insight into the pathogenesis of those juvenile patients.

P1‐59

Juvenile dermatomyositis in a 1‐year‐and‐9‐months‐old boy

Jariya Waisayarat¹; Chinnawut Suriyonplengsaeng²; Chaiyos Khongkhatithum³

¹Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ²Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Rd., Bangkok, Thailand; ³Department of Pedriatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Introduction: Juvenile dermatomyositis is a subtype of inflammatory myopathies with affected patients below 18 years of age. The average age onset is 5 to 14 years with the median age at 7 years. The authors report the very young case of juvenile dermatomyositis.

Clinical summary: A 1‐year‐and‐9‐months‐old boy presented with progressive proximal muscle weakness of upper and lower extremities for 4 months. The patient developed Gottron's papule and heliotrope on of both hands, feet and upper eyelids since 1 year old. He had difficulty rising from the sitting position or raising his arms over his head. He could not walk unassisted, nor could he turn his body or lift his neck. No dysphagia or aspiration was noted. Physical examination showed the heliotrope rash on both upper eyelids and malar rash without nasal sparing. His neurologic examination showed normal extraocular muscles movement and no neurological deficit/localizing signs. Motor power revealed proximal muscle weakness with normal muscle tone. Deep tendon reflexes were normal throughout. He was the second child of the family. No history of the neuromuscular disorder in his family. He had average growth and development before this episode of disease.

Pathological findings: The muscle biopsy reveals perifascicle atrophy and findings which compatible with juvenile dermatomyositis. Immunohistochemistry(MAC and MHC‐I) supports the diagnosis.

Conclusion: To our knowledge, this is the youngest case of juvenile dermatomyositis in Thailand.

P1‐60

Granulomatous myositis associated with anti‐PD‐1 antibody

Naohiro Uchio¹; Kenichiro Taira¹; Chiseko Ikenaga¹; Atsushi Unuma¹; Masato Kadoya²; Akatsuki Kubota¹; Jun Shimizu¹; Tatsushi Toda¹

¹Department of Neurology, Graduate School of Medicine, The University of Tokyo; ²Department of Neurology and Anti‐aging Medicine, National Defense Medical College

Introduction: Immune‐related adverse events (irAEs) are harmful effects associated with immune checkpoint blockers typified by anti‐programmed death‐1 (PD‐1) and ‐programmed death ligand 1 (PD‐L1) monoclonal antibodies (Abs). The skeletal muscle is a target tissue of irAEs, but the immunopathogenesis of muscle destruction remains unclarified. Here, we report two cases of granulomatous myositis following anti‐PD‐1 therapy.

Clinical summary: Case 1. A 79‐year‐old woman with lung adenocarcinoma developed proximal limb weakness following nivolumab treatment. Her creatine kinase (CK) level was 1,638 IU/L. Myositis‐specific autoantibodies (MSAs) and anti‐acetylcholine receptor (AChR) Ab were negative. Needle electromyography showed spontaneous activities. Case 2. A 70‐year‐old man who received pembrolizumab and axitinib for renal cell carcinoma developed left ptosis, diplopia, and weakness with myalgia in his neck and left shoulder. Laboratory tests showed a CK level of 1,832 IU/L, positivity for anti‐AChR Ab, and negativity for MSAs. Needle electromyography and repetitive nerve stimulation were normal.

Pathological findings: Case 1's muscle biopsy showed patchy mononuclear cell infiltrates and granuloma formation in muscle fascicles. In the granulomas, both M1 and M2 macrophages were abundant. PD‐1+ cells were scattered in the granulomas and PD‐L1 was upregulated on the non‐necrotic fibers around the granulomas. CD8+ T‐cells invading non‐necrotic fibers were also observed. Case 2 showed findings similar to those of Case 1 and giant cells in the granulomas.

Conclusion: Granulomatous myositis is one characteristic phenotype of irAE with anti‐PD‐1 antibody. The PD‐1 immune checkpoint pathway may be involved in the aberrant macrophage activation.

P1‐61

Macrophage and chronic Graft‐versus‐host‐disease myositis. A clinicohistopathologic study

Atsushi Unuma¹; Naohiro Uchio¹; Akatsuki Kubota¹; Tsuneyo Mimori²; Jun Shimizu¹; Tatshushi Toda¹

¹Department of Neurology, Graduate School of Medicine, The University of Tokyo; ²Department of Rheumatology and Clinilal Immunology, Graduate School of Medicine, The University of Kyoto

Introduction: The pathology of chronic graft versus host disease (cGVHD) myositis is not well understood, but infiltration of CD8+ cells has been reported. In recent years, involvement of macrophages has been reported in cGVHD. Macrophages are roughly classified into M1‐like acting on inflammation and M2 like anti‐inflammatory. The involvement of macrophages in the chronic GVHD myositis is unknown.

Methods: From our myositis biopsy database from January 2000 to March 2018, we identified 9 patients with cGVHD. We collected clinical information by reviewing the patients’ clinical records. For pathological analysis, frozen muscle specimens were processed for immunohistochemistry including staining for CD11c (M1 macrophage) and CD163 (M2 macrophage). We assessed the amount of CD11c + or CD163 + cells semi‐quantitatively.

Results: Patients were 7 women and 2 men. The serum CK was normal in 3 patients and elevated in 6 patients (239 to 9194 IU/L). Myositis specific antibodies were negative in all patients. The amount of necrotic fibers and inflammatory cells was various; no to mild (n=6) and severe (n=3). All patients showed over expression of MHC‐1 on muscle fibers. In three patients with severe inflammation, CD11c+ cells but not CD8+ lymphocytes, were surrounding and/or invading non‐necrotic fibers. On the other hand, CD163+ cells were diffusely distributed in perimysium and endomysium.

Conclusions: The clinical and pathological features of cGVHD myositis were heterogeneous. The three patients with elevated very high serum CK and frequent CD11c macrophages infiltration in endomysium suggests a subtype of cGVHD myositis.

P1‐62

Abundant cytoplasmic bodies in myotendinous junctions

Yasushi Oya¹; Ichizo Nishino^2,3

¹Dept of Neurol, Natl Center Hosp, Natl Center of Neurology & Psychiatry, Japan; ²Medical Genome Center, NCNP; ³Dept of Nerumuscular Res, Natl Inst of Neurosci, NCNP

Introduction: Nemaline and cytoplasmic bodies are found in normal myotendinous junctions. However, abundant cytoplasmic bodies in myotendinous junctions might be abnormal.

Methods: Retrospective study in cases with cytoplasmic bodies, which were not assumed diagnostic at first, because of existence of myotendinous junctions in the section.

Results: Two cases were found. Case 1. A 77‐year‐old man presented with distal neuropathic leg muscle atrophy and lumbar paraspinal muscle atrophy. Anti‐GalNAc GD1a IgG antibody was positive (++). IVIg was not effective. Needle EMG showed single fiber spontaneous abnormalities and decreased motor units. Nerve conduction studies showed markedly low amplitude of M waves and mildly slow motor nerve velocity in the tibial and peroneal nerves, but sural nerve was normal. Peroneus muscle was biopsied with sural nerve. There was grouped atrophy, but myopathic changes with disorganization of intermyofibrillar networks was prominent. Cytoplasmic bodies and nemaline bodies were found beyond myotendinous junction. Sural nerve was within normal. BAG3 mutation was found. It was difficult to detect myopathic changes by neurophysiological methods. Case 2. Semitendinosus was biopsied in a 32‐year‐old man with distal myopathy. Rimmed vacuoles were frequent. Muscle fibers with cytoplasmic bodies were mostly hypertrophic and scattered. TTN mutation was found.

Conclusion: Abundant cytoplasmic bodies found in muscle fibers can be abnormal even if there are myotendinous junctions in the sections.

P1‐63

An autopsy case of myotonic dystrophy combined with idiopathic normal pressure hydrocephalus

Chigusa Watanabe¹; Takako Makino¹; Tomohito Sugiura^1,2; Masahiro Higaki¹; Yoshiro Tatiyama³

¹Department of Neurology, Hiroshimanishi Medical Center; ²Department of Neurology, Kure Medical Center and Chugoku Cancer Center; ³Department of Pathology, Hiroshimanishi Medical Center

Introduction: Myotonic dystrophy is a hereditary neuromuscular disorder with multisystem involvement. Hydrocephalus is detected uncommonly in adult form of myotonic dystrophy, but idiopathic normal pressure hydrocephalus is rare as a late complication of the disease. We report an autopsied case of myotonic dystrophy combined with idiopathic normal pressure hydrocephalus.

Clinical summary: She was not good at physical exercise, since she was adolescence. In her forties, she felt difficulties in walking and became fall down easily. At the age of 51, she was diagnosed as myotonic dystrophy. She began to use a wheelchair for about 60 years old. At the age of 64, an enlargement of the ventricle was pointed out by CT. At the age of 65, a decline in cognitive function and daily activities was noted, and progressive ventricular enlargement and narrowing of the subarachnoid space of the supratentorial convexity were detected by MRI. Tap test was performed and the activities of daily living and cognitive function were improved. Shunt operation was not performed, as she did not accept it. At the age of 66, she died of respiratory failure.

Pathological findings: Fixed brain weighed 1190g. Mild demyelination was noted in the frontal lobes. Arteriolosclerosis accompanied by gliosis in the white matter were seen. Neurofibrillary tangles and AT‐8 positive neurons were scattered in the limbic system, striatum, substantia nigra. Amyloid beta was not detected immunohistochemically.

Conclusion: We assume that age‐related pathomechanism of myotonic dystrophy might play a role in the development of NPH.

P1‐64

Phosphorylated TDP‐43 (pTDP‐43) aggregates in the axial skeletal muscle of patients with sporadic and familial amyotrophic lateral sclerosis

Matthew Daniel Cykowski; Suzanne Z Powell; Joan W Appel; Anithachristy S Arumanayagam; Andreana L Rivera; Stanley H. Appel

Houston Methodist Hospital

Introduction: Muscle atrophy and weakness are core features of amyotrophic lateral sclerosis (ALS). Studies in ALS patients and animal models have provided evidence that muscle plays an active role in the disease.

Methods: We studied 148 muscle specimens from 57 ALS patients for phospho‐TDP‐43 (pTDP‐43) inclusions in appendicular (quadriceps, deltoid) and axial (diaphragm, paraspinous) groups. p62/ sequestosome‐1 and FUS inclusion pathologies were also examined and in a subset of samples electron microscopy was performed. These samples were contrasted with 25 non‐ALS samples with neurogenic atrophy, including samples of inclusion body myositis (IBM). SQSTM1 and TARDBP gene expression was examined in ALS, IBM, and atrophy samples. Pathologic findings were associated with salient disease characteristics in ALS, such as disease duration and genetic status.

Results: pTDP‐43 myofiber inclusions were identified in 19 ALS patients (33.3%) in 24 samples (16.2% of blocks screened). pTDP‐43 pathology was significantly more common in axial than appendicular muscles in ALS (P = 0.0087) and was not associated with pertinent clinical, genetic, or nervous system TDP‐43 pathologic data. Among non‐ALS samples, pTDP‐43 inclusions were seen only in IBM, where they were more diffuse than in ALS (P = 0.007). p62/ sequestosome‐1, but not FUS, labeling was seen in pTDP‐43‐positive foci in ALS and IBM and both groups showed significant up‐regulation of TARDBP and SQSTM1 expression.

Conclusions: These findings suggest that the impaired clearance of misfolded proteins in ALS, recognized in motor neuron degeneration, may play an important role in pTDP‐43 pathology in ALS muscle.

P1‐65

Anaplastic medulloblastoma with multilineage differentiation in Indian subcontinents: a case report

Suresh Babu¹; Madhu Kumar¹; Atin Singhai¹; Rashmi Kushwaha¹; Chanchal Rana¹; Uma Shanker Singh¹; Ashutosh Kumar¹; Nuzhat Husain²; Anil Chandra³

¹Department of Pathology, King George Medical University, Lucknow, India; ²Department of Pathology, RMLIMS, Lucknow, India; ³Department of Neurosurgery, king George Medical University, Lucknow, India

Introduction: Medulloblastoma with multilineage differentiation is a rare variant with poor prognosis. Medulloblastoma is the most common malignant brain tumor of childhood with predilection for cerebellar vermis. Peak age is 7 years and metastasizes via CSF. Medulloblastoma may have the potential to differentiate into neuronal, astrocytic, myogenic, lipomatous or melanotic types. Very few cases of simultaneous multipotent differentiation are known. Here we present a case of anaplastic medulloblastoma showing multilineage differentiation. This case suggests multipotent stem cells origin of medulloblastoma.

Clinical summary: 21 years male presented with nausea, vomiting and on&off schizures. No previous medical and surgical history. Haemogram was unremarkable. MRI revealed heterogeneously enhancing posterior fossa tumor arising from fourth ventricle.

Pathological findings: Light microscopy demonstrated cellular neoplasm with morphologically distinct components. There was admixture of closely packed anaplastic cells with round to oval hyperchromatic nuclei, scant cytoplasm, occasional rosettes along with large pleomorphic rhabdoid cells having eccentric nuclei and brightly eosinophilic cytoplasm. The third component consisted of cells with small, hyperchromatic nuclei and scant cytoplasm in a fibrillary background. Mature ganglion cells, melanotic tumor cells and frequent mitoses were also present. Immunohistochemistry revealed diffuse expression of GFAP with focal expression of Synaptophysin, NSE, Desmin and HMB45. Thus a final diagnosis of medulloblastoma with myogenic, neuronal, astrocytic, and melanotic differentiation was given. Unfortunately the patient died within 2 months of radiotherapy.

Conclusion: Histopathology and Immunohistochemistry play important role in diagnosis and subtyping. Their exact histogenesis is unclear. Definitive characterization of each medulloblastoma subtype may improve prognosis.

P1‐66

Genomic Alterations and Molecular Subgroups in Atypical Teratoid/Rhabdoid Tumors: The Medical University of Vienna (MUV) Experience

Christine Haberler¹; Thomas Stroebel¹; Marcel Kool^2,3; Thomas Czech⁴; Monika Chocholous⁵; Christian Dorfer⁴; Irene Slavc⁵

¹Medical University of Vienna, Institute of Neurology; ²Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ) and Division of Pediatric Neurooncology of the German Cancer Research Center (DKFZ), Heidelberg, Germany; ³German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany; ⁴Department of Neurosurgery, Medical University of Vienna, Austria; ⁵Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria

Background: Atypical teratoid/rhabdoid tumors are characterized by biallelic inactivation of the SMARCB1/INI1 gene, and may occur sporadically or within the setting of a rhabdoid predisposition syndrome. Three distinct molecular subgroups (ATRT‐TYR, ATRT‐MYC, ATRT‐SHH) have been defined. Patient outcome is in general poor, however, improved patient outcome could be achieved with an intensive multimodal therapy developed at the MUV.

Methods: Tumor tissues and constitutional DNA from 16 patients treated at the MUV for primary or recurrent tumors were analyzed using immunohistochemistry, MLPA, Sanger sequencing and 850K methylation arrays. Patient age at diagnosis ranged between 3 months and 22 years. 5 were females, 11 males. Tumor location was in 10 patients supratentorial (ST) and in 6 posterior fossa (PF).

Results and conclusion: In 8 patients, homozygous deletions of the SMARCB1/INI1 gene were observed. In 3 patients, the combination of a coding sequence mutation and a deletion was found. In 5 tumors only one hit was detectable within the tumor tissue (4 deletions, 1 mutation). Molecular subgroups could be determined in 13 patients and revealed 6 ATRT‐SHH (5 ST/1 PF), 4 ATRT‐TYR (all PF) and 3 ATRT‐MYC (all ST). In 3 patients, 1 ATRT‐MYC, ‐SHH and ‐TYR respectively, a germline alteration was found, including 2 deletions and 1 coding sequence mutation. 11 patients, including 1 patient with germline mutation are alive, 3 patients died of disease, 1 patient died of secondary glioblastoma and 1 patient from sepsis. The documentation of genotype/phenotype correlations is important to detect patients who might have an improved survival.

P1‐67

Congenital central nervous system tumors: a mono‐institutional series of 51 consecutive patients

Anna Maria Buccoliero¹; Chiara Caporalini¹; Barbara Spacca²; Lorenzo Genitori²

¹Pathology Unit, Meyer Hospital, Florence Italy; ²Neurosurgical Unit, Meyer Hospital, Florence Italy

Congenital central nervous system (CNS) tumors are rare and histologically heterogeneous. Their incidence is 1.1‐3.4 per million live births depending on the definition of congenital used. We present a mono‐institutional series of 51 consecutive CNS tumors diagnosed within the first year of age. The predominant age and gender were ≤ 4 months (23, 45%) and male (35, 69%). Thirty‐eight (74%) tumors were supratentorial. The encountered tumors were astrocytomas (18, 37%), embryonal tumors (12, 24%), neuronal‐glial tumors (8, 16%), choroid plexus tumors (8, 16%), teratomas (2, 4%) and ependimomas (3, 4%). Two of 2 (100%) teratomas and 9 of 12 (75%) embryonal tumors were diagnosed within 4 months of age. Three of 3 (100%) ependymomas, 6 of 8 (75%) mixed neuronal‐glial tumors, 5 of 8 (62%) choroid plexus tumors and 11 of 18 (61%) astrocytomas affected children ≤ 4 months old. Eighteen (35%) patients were died (median survival 18 months, range 1‐98 months), 17 (33%) were alive and well (median survival 68 months, range 24‐114 months), 14 (27%) were alive with disease (median survival 31 months, range 7‐76 months), 2 (4%) was lost at the follow‐up. Most frequent tumor among died, alive and well or alive with disease patients were respectively embryonal tumor (7, 39%), choroid plexus papilloma (6, 35%) and low grade astrocytoma (6, 40%). Congenital CNS tumors frequently affect male and are supratentorial. They encompass numerous histotypes with different frequency depending on the age. Embryonal tumors predominate in short survivors patients.

P1‐68

A clinical diagnostic challenge: cranial nerve and leptomeningeal involvement by Atypical Teratoid/Rhabdoid Tumor (AT/RT) in a 15‐month‐old male infant presenting with lip swelling

Fahd Mayouf Al Sufiani¹; Ali Hasan AlAssiri¹; Sarmad Al‐Karawi²

¹Pathology and Laboratory Medicine, King Abdulaziz Medical City; ²Pediatric Neurosurgery, King Abdullah Specialist Children Hospital

Introduction: Atypical Teratoid/Rhabdoid Tumor (AT/RT) is an aggressive embryonal CNS tumor characterized by loss of SMARCB1 or SMARCA4 genes. AT/RT occur most frequently in the posterior fossa of young children with signs and symptoms of increased intracranial pressure. In this report, we describe a male infant with orofacial swelling associated with cranial nerve and leptomeningeal AT/RT.

Clinical summary: An otherwise healthy 15‐month‐old male infant presented with 2 months history of lip swelling. The swelling occurred suddenly in the left side of the upper lip. Parents reported on and off fever as well as facial asymmetry. Infectious workup ruled out herpes which prompted a tissue biopsy from the lip lesion. Microscopically there is only an ulcer and granulation tissue. Multidisciplinary team approach was initiated to rule out infectious, inflammatory, or neoplastic processes. While in hospital, the baby became lethargic and brain MRI demonstrated a hydrocephalus with extensive leptomeningeal and cranial nerve enhancement. There was also a dural based enhancement in the left cerebellopontine angle. An urgent ventricular shunt was performed. Cerebrospinal fluid cytology analysis showed no malignant cells. Decision was made to target the meningeal enhancement for tissue biopsy.

Pathological findings: Biopsy from cerebral cortex revealed expanded subarachnoid space by sheets of small round blue cells. The neoplastic cells immunoreact positively for vimentin, smooth muscle actin and CD99 with lost nuclear staining for INI1. Therefore the diagnosis of AT/RT was confirmed.

Conclusion: We hereby describe a very unusual manifestation of AT/RT with an isolated cranial nerve paresis/paralysis in a very young child.

P1‐69

Grading of Meningeal Solitary Fibrous Tumors/Hemangiopericytomas: Prognostic Value of the Marseille Grading System in a Cohort of 132 Patients in correlation with molecular data

Nicolas Macagno^1,2; Rob Vogels^3,4; Romain Appay^1,5; Carole Colin⁵; Karima Mokhtari⁶; Benno Kusters^3,7; Pieter Wesseling^8,9; Dominique Figarella‐Branger^1,5; Uta Flicke^3,9; Corinne Bouvier^1,2

¹Department of Pathology and Neuropathology, Timone Hospital, AP‐HM Marseille, France; ²INSERM UMR 910, Aix‐Marseille University (AMU), Marseille, France; ³Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands; ⁴Department of Pathology, Stichting PAMM, Eindhoven, The Netherlands; ⁵CNRS UMR 7051, Aix‐Marseille University (AMU), Marseille, France; ⁶Department of Neuropathology, Pitie‐Salpetriere Paris, France; ⁷Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands; ⁸Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; ⁹Pathology, Princess Maxima Center for Pediatric Oncology, Utrecht, and University Medical Center The Netherlands

Introduction: The finding that meningeal Solitary Fibrous Tumors (SFTs) and meningeal Hemangiopericytomas (HPCs) are both characterized by NAB2‐STAT6 gene fusion pushed their inclusion in the WHO 2016 Classification of tumors of the central nervous system (CNS) as different manifestations of the same entity. However, it is presently unclear whether the grading criteria are still adequate. Also, the prognostic value of molecular characteristics of CNS SFTs/HPCs is presently unclear.

Methods: We investigated the prognostic value of an updated version of the Marseille Grading System (MGS), of different NAB2‐STAT6 fusion variants and of Telomerase Reverse Transcriptase (TERT) promoter mutation in a retrospectively collected cohort of 132 primary meningeal SFTs/HPCs.

Results: 73 cases (55%) were MGS I, 50 cases (38%) MGS II, and 9 cases (7%) were MGS III. In multivariate analysis, extent of surgery, mitotic activity ≥5/10 High Power Fields (HPFs), MGS I, and MGS III were independent prognostic factors for progression free survival, while necrosis, MGS III, and radiotherapy were independent prognostic factors for disease specific survival. Although the NAB2ex6‐STAT6ex16/17 type of fusion was significantly more frequent in MGS II and III tumors (p=0.004), there was only a trend for worse prognosis in cases with this fusion type (p=0.172). TERT promoter mutation had no prognostic value.

Conclusion: This study shows that the combination of histologic criteria used in the updated MGS (mitotic activity ≥ 5/10 HPF and necrosis) is valuable for grading meningeal SFTs/HPCs. No clear prognostic value was found for NAB2‐STAT6 fusion type nor for TERT promoter mutation.

P1‐70

Lack of H3K27 hypomethylation in pediatric meningiomas

Angus Toland¹; Melike Pekmezci²; Sonika Dahiya¹

¹Department of Pathology, Washington University in St. Louis, ²Department of Pathology, University of California San Francisco

Modifications of histone H3 at lysine K27 are of interest in oncology due to their prognostic and potential therapeutic implications. Since hypomethylation has been associated with a worse overall (OS) and recurrence‐free survival (RFS) in adult meningiomas, we sought to determine if this association exists for pediatric tumors as well. Clinical data from patients aged ≤17 with a pathologic diagnosis of primary meningioma between the years 1989‐2017 was collected. Tumors were graded based on WHO 2016 criteria. Immunohistochemical staining for H3K27 trimethylation (H3K27me3) was interpreted as positive (endothelial and tumor cell staining) or negative (endothelial staining only). The Kaplan‐Meier log‐rank method and Fisher exact test were used to determine relationships to OS, RFS, sex, NF2, methylation status, and grade. Clinical data from 35 patients was collected. Median patient age was 12 years (range 2‐17). Fourteen patients had a clinical diagnosis of neurofibromatosis type 2 (NF2). There were 18 Grade I (51.4%), 13 Grade II (37.1%), and 4 Grade III (11.4%) tumors. Tissue was available for 29 patients. There were no significant differences in OS or RFS for grade, NF2, or sex. Complete loss of H3K27me3 staining was not observed in any of the tumors. Though H3K27 hypomethylation has been associated with reduced OS and RFS in an adult population, our study did not demonstrate hypomethylation in 29 pediatric meningiomas. This may suggest a distinct tumor biology for pediatric and adult tumors. However, larger studies are necessary to confirm these findings and further elaborate the role of epigenetics in pediatric meningiomas.

P1‐71

Large dural based mass with bony remodeling in a 16 year old: An IgG4 related pseudotumor mimicking lymphoplasmacyte‐rich meningioma

Aruna Nambirajan¹; Tripti Nakra¹; Vaishali Suri¹; Kanwaljeet Singh²; Ajay Garg³; Mehar Chand Sharma¹

¹Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi; ²Department of Neurosurgery, AIIMS, New Delhi; ³Department of Neuroradiology, AIIMS, New Delhi

Introduction: IgG4 related disease is an autoimmune process that presents with tumefactive lesions characterized by storiform fibrosis, a dense lympho‐plasmacytic infiltrate rich in IgG4 positive plasma cells, obliterative phlebitis, and often elevated serum IgG4 levels. CNS IgG4 related disease occurs as hypophysitis, hypertropic pachymeningitis or rarely as intraparenchymal lesions. We present a rare instance of IgG4 related hypertrophic pachymeningitis presenting as a dural pseudotumor mimicking meningioma.

Clinical summary: A 16 year old male presented with focal seizures for last 5 months. Imaging revealed a large extra‐axial contrast enhancing mass lesion in left frontoparietal region with focal calvarial thickening.

Pathological findings: Histopathology revealed a fibrosclerotic lesion involving dura with polymorphic infiltrate of plasma cells, mature lymphocytes, histiocytes, occasional eosinophils and few meningothelial whorls. Immunohistochemical work up excluded the possibilities of meningioma, lymphoproliferative neoplasms and histiocytic lesions. Majority of plasma cells were IgG4 positive with IgG:IgG4 ratio of more than 50%. Based on overall features final diagnosis of IgG4 related inflammatory pseudo‐tumor was rendered.

Conclusion: IgG4 related tumefactive lesions of the CNS are under‐recognized. Identification requires appropriate work up to exclude commoner mimics. They show excellent response to steroids and steroid sparing drugs. Documentation of such cases is essential to improve understanding.

P1‐72

A case of Xanthomatous meningioma

Maki Iida¹; Shiro Tsujimoto¹; Takami Masuo¹; Yukinori Shigematsu¹; Takahiro Inoue¹; Ryutaro Furudate²; Saburo Yagishita³

¹Dept. of Pathology, Yokosuka General Hospital UWAMACHI; ²Dept. of Neurosurgery, Yokosuka General Hospital UWAMACHI; ³Dept. of Neurology, Sagamihara National Hospital

Introduction: Xanthomatous meningioma is a very rare subtype of Grade 1 metaplastic meningioma, in 2016 WHO classification of Central nervous system. We present this case, along with a literature review.

Clinical summary: A 70‐year‐old Japanese female, admitted for generalized seizure. Magnetic resonance imaging demonstrated a well‐demarcated, homogeneously and brightly contrast enhancing mass, measuring 3x2.5x2.2 cm located in the fornix of left frontal lobe. It showed a dural tail sign. Cerebral artery embolization was performed before tumorectomy. Tumor revealed demarcated yellow‐tan colored, attached to the dura.

Pathological findings: Tumor was consisted of meningothelial cell proliferation and numerous xanthomatous changed cells. Scattered Psammomatous bodies and many hyalinous vessels were excisted. Mitosis was rare and necrosis was absent. The xanthomatous tumor cells showed immunoreactivity for epithelial membrane antigen and vimentin. MIB‐1 stained less than approximately 1% of the tumor cells.

Conclusion: We diagnosed this case as Xanthomatous meningioma, WHO Grade I. The patient was followed for 14 months without any evidence of recurrence.

P1‐73

Hypertrophic pachymeningitis accompanying lymphoplasmocyte‐rich meningioma‐a case report

Lei Liu¹; Jianguo Liu²; Dehong Lu³; Qiuping Gui⁴; Jiawei Wang^1,5

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Neurology, Naval General Hospital of the Chinese People's Liberation Army; ³Department of Pathology, Xuanwu Hospital, Capital Medical University; ⁴Department of Pathology, General Hospital of Chinese People's Liberation Army; ⁵Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: Hypertrophic pachymeningitis is a rare chronic fibrosing inflammatory process involves cerebral and/or spinal dura mater. Its underlying cause varies, including neoplasm. Lymphoplasmocyte‐rich meningioma is also a rare histological subtype of meningioma with relatively good prognosis. The combination of both entities has seldom been reported.

Methods: Case report.

Results: A 41‐year‐old woman was present for admission after 3 years of bilateral hearing loss and 1 year of bilateral vision loss.Brain MRI reveal thickened and contrast‐enhanced dura of tentorium cerebelli, bilateral internal acoustic meatus,cavernous sinus and optic nerve sheath. Her CSF showed elevated white blood cells uo to 504 per microliter and protein 166mg per deciliter. Her serum interferon γ release assay was also positive. Other laboratory tests were normal. A biopsy was performed for suspicious chronic tuberculosis meningitis. Pathologically, the specimen showed fibrous tissue hyperplasia,lymphoplasmacytic infiltration, scattered Russell bodies and meningothelial nests. Immunohistochemistry showed CD3,CD20,CD38,CD138 and EMA were all positive.Ki67 index was less than 5 percent.IgG was positive but IgG4 negative. The diagnosis of hypertrophic pachymeningitis accompanying lymphoplasmocyte‐rich meningioma was made.

Conclusion: Hypertrophic pahcymeningitis is a chronic inflammatory disorder of the dura matter that may cause multiple neurological deficits. When the laboratory evaluation for its underlying cause is uncertain,a prompt biopsy should be considered.

P1‐74

Tumour metastasis to meningioma: report of a challenging case

Po Yin Tang¹; Ming Lee¹; Xin Min Cheng¹; Siang Hui Lai^1,2,3

¹Department of Anatomical Pathology, Singapore General Hospital; ²Education Office, Duke‐Nus Medical School; ³Singhealth Tissue Repository, Singhealth

Tumour metastasis to meningioma: report of a challenging case Introduction The occurrence of tumour to tumour metastasis is generally uncommon. In the central nervous system, the most common recipient tumour is meningioma. In a recent review of the literature, 144 cases of tumour to meningioma were reported. Clinical Summary A 63 year old Chinese lady presented with visual blurring in the right eye. There was no other significant history noted. Radiology showed extra‐axial T2 hypointense and enhancing mass centered over the right anterior clinoid, extending superiorly into the right frontal lobe. Pathological Findings At frozen section, the lesion demonstrated predominantly papillary features and myxoid areas. There are also areas composed of spindled cells with whorl formations, in keeping with a meningothelial neoplasm. Paraffin section of frozen remnant and additional tissue submitted revealed glandular formation with cribriform nests and papillary tufts, associated with a myxoid background and areas resembling conventional meningioma. Both components were immunoreactive for EMA. A papillary meningioma was considered, with differential of metastasis involving a meningioma. A subsequent postoperative scan of the thorax showed multiple lung nodules. Additional immunohistochemistry confirmed metastatic adenocarcinoma elements positive for CK7, TTF1 and NapsinA, while the meningioma component was negative. The final diagnosis is that of a metastatic adenocarcinoma of the lung involving a WHO Grade I meningioma. Conclusion In summary, we present a case report of a metastatic lung adenocarcinoma involving a low grade meningioma. Pathologists, radiologists and neurosurgeons should be aware of this diagnostic pitfall.

P1‐75

Intracranial angioleiomyomas: report of 4 rare cases

Yong‐Juan Fu; Yue‐Shan Piao; De‐Hong Lu

Department of Pathology, XuanWu Hospital, Capital Medical University

Introduction: Angioleiomyomas are benign, mesenchymal soft tissue tumours. Intracranial angioleiomyomas are extremely rare. We report 4 Chinese cases of intracranial angioleiomyomas.

Clinical Summary: The lesions of present 4 cases located in the skull base, parasagittal and parafalcine. The neuroradiologic features of these lesions were indistinctive, and they were all misdiagnosed before surgery.

Pathological findings: Histopathologically, these lesions consisted of thick‐walled vessels blending with spindle cells, which were positive for vimentin, desmin and smooth muscle actin, while negative for cytokeratin and HMB45. Cytological atypia and necrosis were hardly observed. And, the Ki‐67 labelling index were less than 2%.

Conclusion: Although rare, angioleiomyomas should be considered as a differential diagnosis of meningioma and other mesenchymal, non‐meningothelial tumours of the central nervous system.

P1‐76

Central nervous system marginal zone B‐cell lymphomas involving brain or spinal parenchyma: clinicopathological study of eight cases

Yasuo Sugita¹; Takuya Furuta¹; Satoru Komaki¹; Koichi Ohshima¹; Hajime Miyata²; Masashi Watanabe³; Akiyoshi Kakita⁴; Hitoshi Takahashi⁴; Shinichi Okonogi⁵; Hiroyuki Masuda⁵

¹Department of Pathology, Kurume University School of Medicine; ²Department of Neuroathology, Research Institute for Brain and Blood Vessels‐AKITA; ³Department of Neurology, Ehime Prefectural Central Hospital; ⁴Department of Pathology, Brain Research Institute, Niigata University; ⁵Department of Neurosurgery Omori, Toho University

Introduction: Marginal zone B‐cell lymphomas (MZBCL) are non‐Hodgkin lymphomas arising from postgerminal center marginal zone B‐cells. MZBCL are subclassified into extranodal‐, nodal‐, and splenic MZBCL. Intracranial MZBCL, one of the extranodal examples, typically present as a solitary dural mass. MZBCL involving the central nervous system parenchyma (MZBCL‐CNSP) are, however, extremely rare, and their clinicopathological features are not well characterized.

Methods: We assessed clinocopathological feature of 8 MZBCL‐CNSP cases (86, 53, 46, 49, 43, 68, 58, 60 years old, 6 males and 2 females). MRIs showed a solitary lesion in 2 patients and multiple lesions in the brain or spinal cord in 6. Aggressive and indolent clinical courses were recorded in 2 and 4 cases, respectively, and 2 patients remained in remission. Histological and immunohistochemical as well as genetic studies were performed using formalin‐fixed and paraffin‐embedded tissue samples obtained form brain biopsy.

Results: Biopsy specimens of all cases revealed atypical small lymphocytic infiltrates with plasma cells in a predominantly perivascular growth pattern. Atypical cells were positive for CD20, but negative for CD3. In addition, tumor‐infiltrating T cells were prominent. It was, therefore, extremely difficult to differentiate the MZBCL‐CNSP from inflammatory or demyelinating diseases or lymphomatoid glanulomatosis in all cases. However, an analysis of immunoglobulin heavy chain variable region (IgVH) genes was valuable in confirming the diagnosis of MZBCL‐CNSP in all cases.

Conclusion: The results indicate that the MZBCL‐CNSP may not always be clinically indolent. Detection of IgVH gene rearrangement is necessary for the definite diagnosis of MZBCL‐CNSP.

P1‐77

Epstein‐Barr virus‐associated diffuse large B‐cell lymphoma in the patient with temozolomide‐treated glioblastoma: A case report

Yoon Jin Cha¹; Chang‐Ki Hong²; Se Hoon Kim³

¹Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea; ²Department of Neurosurgery, Yonsei University of Medicine, Brain Tumor Center, Gangnam Severance Hospital, Seoul, Korea; ³Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea

Introduction: Temozolomide is a DNA‐alkylating agent fort treatment of glioblastoma (GM). So far, around 10 cases of non‐Hodgkin lymphoma have been reported in glioma patients after temozolomide treatment. Here, we reported a rare case of Epstein‐Barr virus(EBV)‐associated diffuse large B‐cell lymphoma (DLBCL) subsequently developed after glioblastoma treated with temozolomide.

Clinical summary: A 57‐year‐old female patient received gross total removal of GM of left parietal lobe and underwent subsequent concurrent chemoradiation and temozolomide for maintenance. Seven months later, aphasia was developed after 4th cycle of temozolomide. Brain magnetic resonance image (MRI) revealed a newly appeared rim‐enhancing mass in left parietal lobe. As tumor recurrence was suspected, the lesion was surgically removed and diagnosed with EBV‐associated DLBCL. Patient treated with high‐dose methotrexate combined with vincristine and dexamethasone. Six month later from diagnosis of DLBCL, follow up brain MRI revealed T2‐intense lesion in right temporal lobe, and recurrent GM was suspected. Patient is still alive, being treated with salvage radiotherapy.

Pathologic findings: The firstly removed tumor was typical glioblastoma, IDH‐wildtype, harboring palisading necrosis and endovascular proliferation. The secondly developed lesion showed radionecrosis and multiple patchy lymphocytic proliferation. In addition, coagulative necrosis and angiodestructive growth pattern of monotonous lymphocytes were suspicious findings. The lymphocytes were diffusely positive for CD20 and EBV in situ hybridization. Taken together, a diagnosis of EBV‐associated DLBCL was made.

Conclusion: Although rare, secondary lymphoma could be developed during or after temozolomide treatment, might be derived by drug toxicity or induced immunosuppression and EBV infection.

P1‐78

Histopathological features of an autopsied patient with lymphomatoid granulomatosis in the central nervous system

Susumu Ikenoshita¹; Toshinori Oshima¹; Susumu Ohkawara¹; Tsukasa Doki²; Takayuki Kosaka²; Hajime Miyata³; Akiyoshi Kakita⁴; Takaaki Ito⁵; Yasuo Sugita⁶; Yukio Ando²

¹Arao Municipal Hospital; ²Department of Neurology, Graduate School of Medical Sciences, Kumamoto University; ³Department of Neuropathology, Research Institute for Brain and Blood Vessels – AKITA; ⁴Department of Pathology, Brain Research Institute, Niigata University; ⁵Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University; ⁶Department of Pathology, Kurume University School of Medicine

Introduction: Lymphomatoid granulomatosis (LYG) is one of the Epstein‐Barr virus (EBV) ‐associated lymphoproliferative disorders, rarely involving the central nervous system (CNS).

Clinical summary: A 68‐year‐old male developed gait disturbance with falling. Parkinsonism was observed. Levodopa was ineffective against his symptoms. He was clinically diagnosed as multiple system atrophy. Then, he deteriorated and one year after the onset, he suddenly fell into coma followed by status epilepticus. MRI revealed Gd‐enhancing lesions in the left cerebral subcortical white matter, corpus callosum and middle cerebellar peduncles. Approximately 20 months after the onset, he died.

Pathological findings: At autopsy, the brain weighted 1,500 g. Macroscopically, the left cerebral hemisphere was severely swollen. Coronal sections of the cerebrum demonstrated ill‐demarcated grayish and softening lesions mainly in the left cerebral subcortical white matter, corpus callosum, and middle cerebellar peduncle. Microscopically, marked perivascular and parenchymal lymphocytic inflammations with necrosis were noted. Granuloma like‐mass lesions consisting of numerous CD68‐positive macrophages, CD3‐ or CD20‐positive T‐ or B‐lymphocytes and plasma cells with necrosis were also observed. Neither prominent mitotic changes nor viral inclusions were demonstrated. Epstein‐Barr encoding region (EBER) in situ hybridization disclosed positive nuclei of the infiltrating cells.

Conclusions: We reported the autopsy findings of LYG. LYG could be classified as a T‐cell rich, EBV‐associated, B‐cell lymphoproliferative disorder. However, it remained controversial that CNS‐LYG may be a disorder derived from T‐cell monoclonal lymphoproliferation. Further histopathological studies are needed to clarify the histogenesis and prognostic variability on the CNS‐LYG.

P1‐79

An autopsy‐proven case of paraneoplastic lower motor neuron disease due to Waldenstrom's macroglobulinemi

Yasuhiro Suzuki^1,2; Hitoshi Aizawa³; Kento Sakashita¹; Hideaki Kishi¹; Kenta Nomura¹; Kosuke Yoshida¹; Yoko Aburakawa¹; Kenji Kuroda¹; Yasutaka Kakinoki⁴; Takashi Kimura¹

¹Departments of Neurology, Asahikawa Medical Center; ²Departments of Clinical Research, Asahikawa Medical Center; ³Department of Neurology, Tokyo Medical University; ⁴Department of Hematology, Asahikawa City Hospital

Introduction: Waldenstrom's macroglobulinemia(WM) is defined as a lymphoplasmacytic lymphoma that develops in the bone marrow and is characterized by immunoglobulin M paraproteinemia. A few reports have evaluated the association with motor neuron disease(MND) and definitively diagnosed monoclonal paraproteinemia due to WM during an autopsy.

Clinical summary: We report a case of a 77‐year‐old man who developed WM with sensorimotor neuropathy who was pathologically confirmed to have lower MND by autopsy.

Pathological findings: After informed consent for family, Autopsy was done. Whole brain, brain stem, spinal cord, and peripheral nerve were fixed with 4% formalin. Routine hematoxylin and eosin staining and Luxol fast blue were done. Moreover, immunostain by anti‐CD20 antibody, anti‐CD38, and anti‐pTDP‐43 antibody was carried out. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells which included B cells and plasma cells in the lumbar anterior and posterior roots, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, pTDP‐43 antibody positive cytoplasmic inclusions were observed in the motor neurons and astrocytes of hypoglossal nuclei and whole spinal cord.

Conclusion: Although the relationship between WM and lower MND is obscure, we speculate that the paraneoplastic effect or immunological factors due to WM might enhance motor neuron death and degeneration of the posterior funiculus.

P1‐80

Castlemans disease plasma cells type intraspinal and unicentric: report of a case and review of the literature

Eric Eduardo Mendoza; Erick Apo; Janeet Garduno; Eduardo Flores; Laura Chavez

Department of neuropathology, General Hospital of Mexico Dr. Eduardo Liceaga

Introduction: Castlemans disease is a rare lymphoproliferative disorder. The unicentric disease, typical of the hyaline‐vascular type, however, the type of plasma cells can present as a localized mass, approximately 10%, with resolution of symptoms after surgical resection.

Clinical summary: A 51 year old woman who started in 2012 with low back pain, limitation of movements and loss of strength in pelvic limbs. After surgery recovered strength, remitting in August 2016, with paresthesias, making it impossible to walk, decreased thermal sensitivity and pain in both extremities. The physical examination revealed a decrease in thermoalgesic sensitivity of T7 towards caudal. Magnetic resonance imaging shows an intraspinal, extraaxial lesion that compresses the spinal cord at the level of T4‐T5.

Pathological findings: Multiple fragments of light brown tissue and rubbery consistency. The histology shows multiple reactive lymphoid follicles and germinal centers with stainable body macrophages. The interfollicular, paracortical and medullary space are full of monotonous and non‐atypical plasma cells. Immunohistochemistry with reactive pattern for CD20 and CD3 in the germinal centers and the paracortical compartment respectively, CD138 positive in plasma cells, with polyclonal expression for the Kappa and Lambda light chains and negative for HHV8.

Conclusion: Castlemans disease is uncommon and clinically it can be unicentric or multicentric. The plasma cell type is most often multicentric. Histologically, it can have hyperplastic lymphoid follicles and plasma cell mantles without atypia that dilate the sinusoids and that can be found in the paracortical and interfollicular zone. The intraspinal presentation is extremely rare.

P1‐81

Extranodal Rosai Dorfman disease: case with primary involvement in the central nervous system

Eric Eduardo Mendoza; Erick Apo; Janeet Garduno; Luis Manola; Eduardo Flores; Alejandra Zarate; Laura Chavez

Department of Neuropathology, General Hospital of Mexico Dr. Eduardo Liceaga

Introduction: Rosai Dorfman disease is a clinicopathological entity of unknown nature and scarce frequency. It occurs as massive lymphadenopathy with sinus histiocytosis and systemic symptoms such as fever. Exceptionally, it presents as an extranodal entity without lymphatic involvement.

Clinical summary: A 35 year old man who started in 2016 with a slight decrease in the strength of the left thoracic limb, ipsilateral peripheral facial paralysis and a tonic‐clonic seizure episode. The physical examination showed facial asymmetry to the gesticulation with deviation of the mouth corner to the right. Magnetic resonance imaging shows a solid lesion in the right temporoparietal plate dependent on the dura mater. No neck ganglion growths were observed.

Patological findings: Fragment of thickened dura mater and fine granular surface, grayish white color and rubbery consistency. The histology shows substitution of the meningeal parenchyma for mixed inflammatory infiltrate, with formation of lymphoid follicles, eosinophils and abundant clear cytoplasm histiocytes, oval nuclei and fine granular chromatin. In some areas the phenomenon of emperipolesis is observed, without atypical mitoses, necrosis or neoplastic cells. Positive immunohistochemistry for PS‐100 and negative for CD1a.

Conclusion: Rosai Dorfman disease with meningeal disease is a rare entity. In imaging studies, it is usually diagnosed as plaque meningioma. Clinically it presents with focal motor deficits, seizures and headache. The diagnosis is morphological and immunohistochemistry can help rule out neoplastic lesions of lymphoid strain. In most cases surgery is indicated, but in patients with extensive lymph node involvement, corticosteroids and radiotherapy are used as adjuvants.

P1‐82

Chondroblastoma‐like tumor of the skull in a patient with cardio‐facio‐cutaneous syndrome

Danielle Fasciano¹; Rong Li²; Shi Wei¹; Gene P. Siegal¹

¹Department of Pathology, University of Alabama at Birmingham; ²Department of Pathology, Children's of Alabama

Introduction: Cardio‐facio‐cutaneous syndrome (CFCS) is a rare genetic disorder characterized by craniofacial deformities and heterogenous cardiac and cutaneous manifestations. The condition is caused by de novo activating mutations in the RAS/MAPK signaling pathway, including BRAF, MEK1, MEK2, and KRAS. Urothelial carcinoma, embryonal rhabdomyosarcoma and neuroblastoma have been reported in the setting of CFCS.

Clinical summary: Herein we report a chondroblastoma‐like lesion of the skull in a 20‐year‐old man with a clinical diagnosis of CFCS and a long standing history of medically intractable epilepsy. The patient presented with altered mental status, lethargy and vomiting. Imaging studies demonstrated expansion of the left mastoid temporal bone along with a large left temporal intracerebral hematoma. He underwent left temporoparietal craniectomy and debulking of the hemorrhagic tumor.

Pathologic findings: Histologic examination revealed a mixed solid and cystic lesion. The more solid areas exhibited sheets of mononuclear cells, many with nuclear grooves, variably sized multinucleated giant cells and fibrochondroid islands. The latter consisted of blood‐filled cystic spaces lack of endothelial lining and focal unmineralized bone along the cyst walls. FISH analysis for USP6 gene rearrangement was negative. While these features are mostly consistent a chondroblastoma with secondary aneurysmal bone cyst formation, next generation sequencing studies revealed no mutations in H3F3A or H3F3B gene, respectively. However, a p.Q257R mutation located on exon 6 of the BRAF gene characteristic of CFCS was identified.

Conclusion: Patients with CFCS have prevoiusly been noted to have poorly‐defined giant cell‐rich lesions and this may be one such example.

P1‐83

Sellar atypical teratoid/rhabdoid tumor (AT/RT): a clinicopathologically and genetically distinct variant of AT/RT

Satoshi Nakata¹; Sumihito Nobusawa¹; Takanori Hirose²; Junko Hirato³; Youichi Nakazato⁴; Hideaki Yokoo¹

¹Department of Human Pathology, Gunma University Graduate School of Medicine; ²Department of Diagnostic Pathology, Hyogo Cancer Center; ³Department of Pathology, Gunma University Hospital; ⁴Department of Pathology, Hidaka Hospital,

Introduction: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, aggressive tumors of the central nervous system that predominantly affect infants. Although adult AT/RT is rare, accumulated cases have revealed adult‐specific AT/RT in the sellar region. Eighteen previously reported cases of sellar AT/RT exclusively occurred in adults, suggesting biological differences from conventional infant AT/RT. We herein investigated a series of seven sellar AT/RT to clarify the clinicopathological and genetic outlines of this tumor.

Methods: Seven cases of sellar AT/RT were histologically and immunohistochemically assessed. Fluorescence in situ hybridization, direct sequencing, and multiplex ligation‐dependent probe amplification analyses for the INI1/SMARCB1 gene were performed.

Results: All seven cases were adult females, ranging in age from 21‐69 years old. Tumors were histologically characterized by a hemangiopericytoma‐like stag‐horn vasculature within a dense, diffuse proliferation of jumbled cells and a few scattered rhabdoid cells. This vascular pattern is not a common finding in AT/RT and appears to be characteristic histology of sellar AT/RT. Biallelic alterations in the INI1 gene were identified in five out of the six cases analyzed. Four out of the five cases harbored two different mutations, presumably on different alleles (compound heterozygous mutations), and one case of which had a splice‐site mutation. Combined with previous findings, the prevalence of compound heterozygous mutations and splice‐site mutations was significantly higher in sellar AT/RT than in pediatric AT/RT.

Conclusion: Sellar AT/RT represent a clinicopathologically and possibly genetically distinct variant of AT/RT showing characteristic demography, different patterns of INI1 alterations, and histology featured by a unique vasculature.

P1‐84

Thirty Years Experience with Pituitary Adenomas

E Tessa Hedley‐Whyte¹; Brooke Swearingen²

¹Neuropathology, Massachusetts General Hospital, Harbard Univesity; ²Neurosurgery, Massachusetts General Hospital, Harbard Univesity

Introduction: The immunohistochemistry results of resected pituitary adenomas in 1989,1999 and 2008 were compared from a database of 4800 cases (1984‐2017).

Methods: The extent of immunohistochemical reaction to prolactin, human growth hormone, beta sub‐units of FSH, LH,and TSHalpha sub‐unit, ACTH, Mib‐1Cam5.2 and p53 for all pituitary adenomas at MGH since 1987 were recorded on a scale of zero to 3+ (none, scarce, some and many or most). The data from the years 1989. 1999,and 2008 were compared for trends in types of tumors and immunohistochemical investigations.

Results: The numbers of adenomas increased from 65 per year in 1989‐1999 to about 140 per year through 2017. 73, 115 and 124 cases were recorded in 1989, 1999 and 2008. 1989 73 tumors including 12 Cushing (16%),prolactinoma 10(14%),14 acromegaly(19%, ). 1999 115 tumors including 23 Cushing(20%,18F),6 prolactinomas(5%),12 acromegaly(10%,4F). and in 2008 124 tumors including 23 Cushing(20%,22F), 9 prolactinomas(7%), 21 acromegaly (17%,12F). In the three time periods there were no Mib1, p53 or Cam5.2 performed in 1989. Only 8 Mib1 was performed in 1999. In 2008 86 Mib1, 28 p53 and 17 Cam5.2. Five of the latter with a dot‐like pattern.

Conclusion: Construction of this database has enabled recognition of changing patterns of immuno‐histochemical analysis of pituitary adenomas. The most noticeable change was the adoption of Mib1 proliferation index, Cam5.2 between 1999 and 2008. and enabled clinical pathological exploration of adenoma behavior. This database has contributed to many publications.

P1‐85

Histological, MRI and clinical characteristics in patients with IgG4‐related pathology in pituitary gland

Sengul Ahlstrom^1,2; Johan Wikstrom³; Olafur Gudjonsson⁴; Eva Kumlien⁴; Britt Eden‐Engstrom⁵; Olivera Casar‐Borota^1,2

¹Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; ²Department of Clinical Pathology, Uppsala University Hospital, Uppsala, Sweden; ³Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; ⁴Department of Neuroscience, Uppsala University, Uppsala, Sweden; ⁵Department of Medical Sciences, Endocrinology and Metabolism, Uppsala University, Uppsala, Sweden

Introduction: IgG4‐related disease is a multiorgan disease histologically characterised by lymphoplasmacytic infiltration with a high proportion of IgG4‐reactive plasma cells, fibrosis and occasional obliterative phlebitis. IgG4‐related hypophysitis has been increasingly reported. However, diagnostic criteria and whole spectrum of histological changes are still unclear due to limited number of biopsy‐proven cases.

Methods: We have reexamined specimens obtained by pituitary surgery performed at Uppsala University Hospital in the period 2010‐2017 that were originally reported to represent inflammatory changes. An additional specimen was available from dura from a patient who presented with clinical signs of hypophysitis followed by chronic meningitis. Patients with IgG4‐related changes in tissue specimens were selected and their MRI, clinical and histopathological characteristics correlated.

Results: Five pituitary specimens fulfilled histological criteria for IgG4‐related hypophysitis. IgG4‐related pathology has also been confirmed in the dural biopsy. Additional histological changes that are not traditionally related to IgG4 process were identified in all the biopsies. Specific MRI changes suggestive for IgG4‐related pituitary pathology could not be identified. One of the patients had slightly elevated serum IgG4 and extracranial manifestations potentially related to IgG4 process.

Conclusion: Preoperative diagnosis of IgG4‐related hypophysitis is difficult due to lack of specific clinical and MRI features. Patients with IgG4‐related hypophysitis rarely show disease manifestations in other organs. The presence of the histopathological changes not strictly related to IgG4 process suggests the role of organ specific mechanisms that potentially trigger IgG4 cell proliferation and fibrosis. Possibility of the intracranial propagation of the IgG4 process cannot be excluded.

P1‐86

Craniopharyngioma recurrent with extended necrosis (craniopharyngioma apoplexy): two cases reports

Martha Lilia Tena‐Suck¹; Armando Saul Ruiz‐Trevino²; Alma Ortiz‐Plata^2,3; Carlos Sanchez‐Garibay¹

¹Department of Neuropathology, National Institute of Neurology and Neurosurgery; ²Service of Neurosurgery, National Institute of Neurology and Neurosurgery; ³Department of Experimental Neuropathology, National Institute of Neurology and Neurosurgery

Introduction: The term pituitary apoplexy is a less common condition when a pituitary tumor outgrows its blood supply a stroke, describes larger bleeds leading to the sudden onset of symptoms. Little is known about the Craniopharyngioma apoplexy. We presented 2 cases of apoplexy CP.

Clinical Summary: 30‐year‐old woman who for 18 years old has been diagnosed a CP. Until now she has recurred in 6 different times, last one, she was admitted to our hospital with sudden headache, drowsiness and hyponatremia, as a large infiltrating tumor across the skull base and extends through the nose. 60‐year‐old man, with visual disturbance, RMI showed a selar tumor. Total removal was performed. After surgery the patients presented a thalamic infarct and dead. Histological findings: adamantinomatous craniopharyngioma with extensive necrosis, thrombosis, fibrin, and reactive changes of the epithelium were observed in both cases. These changes should take into consideration when we have a highly aggressive tumor. 2th case report illustrates the possible occurrence of intracranial thalamic infarct after surgery induced vasculopathy after CP resection. Lipid thrombosis and thalamic infarct that was considered as complication post‐surgery of CP.

Conclusions: We present two cases with extensive hemorrhage and necrosis, fibrin thrombi and tumor rupture. The first with reactive epithelial changes and the second with thalamic infarction. Unusual conditions of the CP. It is striking that despite being a benign tumor with necrosis shows changes that suggested an interrogation, and histologically and/or being considered as apoplexy.

P1‐87

The Glut family members in association with heat shock proteins in the boundary of craniopharyngiomas. Clinical, histopathological and immunohistochemical correlation

Martha Lilia Tena‐Suck¹; Miguel Fernando Salazar‐Morales²; Marcela Cecilia Mucino‐Bolanos³; Manuel Castillejos‐Lopez⁴; Abel Santamaria‐Del Angel⁵

¹Department of Neuropathology, National Institute of Neurology and Neurosurgery; ²Department of Pathology,High Specialty Naval General Hospital; ³Service of Neurosurgery. Military Central Hospital of Mexico City; ⁴Epidermilogy Department. National Institute respiratory disease; ⁵Laboratory of excitatory monoacid. National Institute of Neurology and Neurosurgery

Introduction: Craniopharyngioma is a rare brain tumor. These lesions have a tendency to recurrence and invade surrounding structures and to recur after an apparently total resection. The Glut family members expressed and controls glucose uptake and metabolism necessary for motility and maturation.

Methods: We examined GLUT (GLUT1, 2, 3, and 4) in correlation with HSP proteins (27, 70, 90 and 94) and lactate dehydrogenase in craniopharyngiomas and to test the hypothesis that recurrent hypoglycemia changes the brain's capacity to utilize different energy substrates and HSPs activation. Clinical, histopathological and immunohistochemistry correlation.

Results: 28 CPs were included in this paper. 12 (43%) were females and 16 (57% were males, the ranged aged was from 17 to 55 yrs (median 31.43 + 10.057) Recurrence in 12 (46%) cases. Glut 1, 3 and IGF immunoexpression was in wet keratin and dystrophic calcification, more observed in recurrence than no recurrence tumors. HSP27 and 70 were positive in astrocytes and Rosenthal Fibers. However, HSP 90, and 94 were higher immunoreaction in wet keratins and dystrophic calcifications. The patients who presented more WK, and DC features showed metabolic syndrome, and glucose dysfunction.

Conclusion: WK and DC correspond to histological structures that remain metabolically active and that stimulate the presence of HSP proteins. This is observed more in recurrent than in non‐recurrent tumors as well as in patients those presented metabolic syndrome. IGF‐I as well as HSP90 and 94 as a glial rescue agent. Glucose metabolism is implicated in brain infiltration and recurrence.

P1‐88

Brain normal adjacent tissue to Craniopharyngioma boundary and oxidative stress expression

Martha Lilia Tena‐Suck¹; Abel Santamaria‐Del Angel²; Alma Ortiz‐Plata³; Francisca Fernandez‐Valverde³

¹Department of Neuropathology, National Institute of Neurology and Neurosurgery; ²Laboratory of excitatory monoacid. National Institute of Neurology and Neurosurgery; ³Laboratory of Experimental Neuropathology, National Institute of Neurology and Neurosurgery

Introduction: Craniopharyngioma is an epithelial tumor of the sellar region with a high survival rate but a high rate of recurrence.

Methods: We analyzed different antibodies involved in oxidative stress and inflammation process in CP, ultrastructure of brain invasion and chemically analyzing of oily content cystic were performed. Clinical, pathological, immunohistochemical correlation.

Results: 28 patients were included, 13 (46%) with recurrence and 15 (54%) presented adjacent brain tissue invasion. Note that cystic contents contained high levels of lipids, cholesterol, glucose, protein, bilirubin, transaminases and low hemoglobin content. Adjacent brain tissue invasion correlated with gender (p = 0.044), OR from 222 to 6730 (1.222), inflammation (p = 0.048), Rosenthal fibers (p = .000), and epithelial rupture (p = .000). Dystrophic calcification form in invasion was positive for recoverin, lactate dehydrogenase, TNF, IFI16, and NFE2L2 and was negative for perilipin and TNFα, nitrotiroxin, e‐NOS, Hif‐1α, GSK3 and negative for GLUT‐4 and NFE2L2. The way to encroach upon wet keratin was positive for recoverin, lactate dehydrogenase, KFϰB, TNF, IFI16, and NFE2L2 and was negative for perilipin and TNF, nitrotiroxin, e‐NOS, Hif‐1α, GSK3 and nitrotiroxin.

Conclusion: The way to infiltrate as single cells was positive for lactate dehydrogenase, TxrR1, TNFα, IFNγ, nitrotiroxin, Hif1α, e‐NOS, GSK3, Glut‐4, NFE2L2, CD71 and perilipin. Conclusions. When tumor cells invade the brain tissue that is performed by the active factors oxidative stress pathway by rupture of basal membrane and oil fluid exit or runoff.

P1‐89

ACTH‐producing pituitary carcinoma. A case report

Hiromi Onizuka¹; Kenta Masui²; Noriyoshi Takano³; Midori Yatabe³; Junichi Yatabe³; Satoshi Morimoto³; Kosaku Amano⁴; Takakazu Kawamata⁴; Tatsuo Sawada²; Noriyuki Shibata²

¹Department of Surgical Pathology, Tokyo Women's Medical University Hospital; ²Department of Pathology 1, Tokyo Women's Medical University; ³Department of Endocrinology and Hypertension, Tokyo Women's Medical University Hospital; ⁴Department of Neurosurgery, Tokyo Women's Medical University Hospital

Introduction: Pituitary carcinoma is extremely rare and strictly defined as a tumor of adenohypophyseal cells with craniospinal dissemination or systemic metastasis. Here, we report an autopsy case of pituitary carcinoma which produced ACTH, with the review of literatures.

Clinical summary: A 79‐year‐old man presented with diplopia and oculomotor nerve palsy. Sellar tumorous lesion was detected by MRI and was clinically diagnosed as meningioma. His neurological symptoms were worsened after gamma knife therapy, and MRI showed the tumor invasion to the cavernous sinus. Transsphenoidal surgery was perfomed and neuroendocrine carcinoma of the sellar region was histologically suspected. Despite the additional chemoradiation, the tumor was enlarged with extensive meningeal dissemination, and he died 2 years after the first symptoms. An autopsy was performed to search for the primary lesion of the tumor.

Autopsy findings: In the sellar region, atypical cells with eosinophilic cytoplasm proliferated in an alveolar pattern. These atypical cells were widely disseminated to the meninges and metastasized to the liver, lung and peripancreatic lymph node. Immunohistochemically, the atypical cells were positive for synaptophysin, CD56 and CK(AE1/AE3), focally positive for ACTH, and negative for GH, PRL, TSH, FSH and LH.

Conclusion: The previous surgical specimen had showed the same immunophenotype as the autopsied one. From the histopathological findings and clinical course, we diagnosed the case as ACTH‐producing pituitary carcinoma.

P1‐90

Agressive behavior of Spindle cell oncocytoma: a case report

Jaquelyne Cruz Ibiapina¹; Karina A. D. Fuzinatto¹; Aline H. S. Camacho^1,2; Cristiane Scaf^2,3; Leandro Kasuki^2,3; Luiz Eduardo Wildemberg^2,3; Nina Ventura²; Paulo Jose da Mata Pereira²; Monica Gadelha^2,3; Leila Chimelli²

¹Divisao De Anatomia Patologica, Instituto Nacional Do Cancer; ²Laboratorio De Neuropatologia E Genetica, Instituto Estadual Do Cerebro Paulo Niemeyer; ³Universidade Federal Do Rio De Janeiro

Introduction: Spindle cell oncocytoma, a non‐neuroendocrine neoplasm of the pituitary gland showing nuclear expression of TTF1, is a rare entity that despite being defined as grade I WHO, may assume malignant and aggressive behavior with multiple relapses and a high proliferative index.

Clinical Summary: A 34‐year‐old man was admitted in March 2017 with unilateral right headache for a year with worsening in recent weeks, progressive ptosis, right III, IV and VI cranial nerves palsy and hypoesthesia of the V. MRI revealed a massive sellar and suprasellar lesion extending into the right cavernous sinus, which was approached via transsphenoidal. A solid and bleeding tumor was partially resected. The lesion, initially treated with radiotherapy, recurred 3 months later and the new CT scan revealed tumor expansion compressing the floor of the third ventricle and remodeling the sellar floor. The patient was re‐operated in December 2017 via frontal craniotomy.

Pathological Findings: Proliferation of cells with predominant fusiform appearance, arranged in bundles, with moderate nuclear pleomorphism. Mitoses were frequent and there were areas of necrosis. Tumor cells were immunopositive for EMA, TTF‐1, GFAP and INI‐1. CAM5.2 and progesterone receptor were negative and Ki67 was 20%. The diagnosis was spindle cell oncocytoma. In the second resection the histology was similar, except for and increased number of polygonal cells and anaplasia, as well as focal chordoid appearances and a ki67 of 40%.

Conclusion: Although this neoplasia has usually a good prognosis, this case, as few others previously reported, showed aggressive histology and clinical course.

P1‐91

Differential diagnostic impact of DNA methylation profiling on brain tumor classification

Jeanette K. Petersen^1,2; Henning B. Boldt^1,2; David Scheie³; Benedicte P. Ulhoej⁴; Maria Gardberg⁵; Rikke H. Dalhrot⁶; Frantz R. Poulsen^2,7; Dr. David Capper⁸; Dr. Andreas von Deimling^9,10; Bjarne W. Kristensen^1,2

¹Department of Pathology, Odense University Hospital, Odense, Denmark; ²Department of Clinical Research,University of Southern Denmark, Odense, Denmark; ³Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; ⁴Department of Pathology, Aarhus University Hospital, Aarhus, Denmark; ⁵Department of Pathology, Turku University Hospital and University of Turku, Turku, Finland; ⁶Department of Oncology, Odense University Hospital, Odense, Denmark; ⁷Department of Neurosurgery, Odense University Hospital, Odense, Denmark; ⁸Department of Neuropathology, Charite ‐ Universitetsmedizin Berlin, Germany; ⁹Department of Neuropathology, Institute of Pathology, Ruprecht‐Karls‐University, Heidelberg, Germany; ¹⁰Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

Introduction: Genome‐wide DNA methylation profiling is a new promising approach for improved brain tumor diagnostics. The potential of this approach has recently been successfully explored by the German Cancer Research Center. We report the diagnostic impact of a DNA methylation‐based classifier tool tested in a clinico‐pathological setting.

Methods: We collected tumor tissue from 135 patients, where the initial diagnoses were inconclusive or where a more precise classification was needed. DNA methylation profiling was performed using the EPIC BeadChip (850K). Data files were generated and uploaded to a DNA methylation‐based classifier tool and matched to a brain tumor reference cohort with more than 2800 CNS tumors covering more than 80 tumor methylation classes. Reports were generated including a classifier score and a DNA copy‐number variation (CNV) profile.

Results: Eighty eight tumors (65%) significantly matched a methylation class. The initial histopathological diagnoses were changed in 24 out of 88 tumors representing a reclassification rate of 27%. This was based on methylation profiling scores representing a match to a specific DNA methylation class as well as CNV changes, immunohistochemical findings and next‐generation sequencing results. A change in WHO tumor grade among the reclassified tumors was observed in 67% of the tumors, with downgrading of 25% and upgrading of 42%.

Conclusion: DNA methylation profiling is a valuable diagnostic tool for tumor classification, especially in cases, where morphological and genetic features are inconclusive. The use of DNA methylation profiling initiated re‐evaluation and incorporation of additional tools leading to more precise brain tumor diagnostics.

P1‐92

A targeted NGS‐based overall solution to support diagnostics and therapy prediction in neurooncology: Considerations for a flexible and cost‐efficient platform choice and panel design

Markus J. Riemenschneider^1,2; Andras Rudolf^1,2; Peter Hau^2,3; Tobias Pukrop^2,4; Oliver Koelbl^2,5; Selim Corbacioglu^2,6; Alexander Brawanski^2,7; Martin Proescholdt^2,7; Julia Lorenz^1,2

¹Department of Neuropathology, Regensburg University Hospital; ²Wilhelm Sander Neuro‐Oncology Unit and Brain Tumor Center, Regensburg University Hospital; ³Department of Neurology, Regensburg University; ⁴Department of Internal Medicine III, Regensburg University Hopsital; ⁵Department of Radiotherapy, Regensburg University Hospital; ⁶Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Regensburg University Hopsital; ⁷Department of Neurosurgery, Regensburg University Hopsital

Introduction: The new WHO classification still poses challenges to many neuropathology labs. Some of the relevant alterations (e.g. C11orf95‐RELA) are hard to assess or complex subclassifications (e.g. for medulloblastomas) are required. Some labs rely on a two‐tiered approach: i) methylation arrays for tumor classification and ii) targeted NGS panel sequencing for identifying actionable mutations. However, high initial investment and annual costs for running two platforms in parallel hinder a fast expansion of the new techniques in the breadth of neuropathology.

Methods/Results: We decided to focus on the sole use of the relatively cost‐efficient Mini‐Seq NGS platform (Illumina). First, we designed a DNA panel (FFPE, HaloPlex, Agilent; no Covaris required) that is suited for detection of DNA mutations, copy number alterations and chromosomal alterations (459 kbp, 58 genes, 4082 SNPs, 98.83% coverage). We successfully used this platform to support tumor classification in astrocytomas, oligodendrogliomas, meningiomas and medulloblastomas and identified actionable targets of clinical use. We then designed a RNA panel (FFPE, Sure Select, Agilent) that detects gene fusions and covers a broad range of alterations particularly relevant to pediatric tumors (e.g. pediatric glioblastomas, ependymomas, CNS PNETs) (148 kbp, coding sequence of 31 genes, 99.88% coverage).

Conclusion: With these two panels we cover the most relevant molecular alterations in the field of neurooncology. The cost‐efficient and flexible single platform approach enables state‐of‐the‐art molecular diagnostics in virtually every neuropathology lab. Functionality is guaranteed for future revisions of the WHO classification as novel biomarkers can be easily included in an adapted panel design.

P1‐93

Molecular subgrouping of gliomatosis cerebri according to the 2016 World Health Organization classification of tumors of the central nervous system

Mi Jung Kwon¹; Yeon‐Lim Suh²; Haeyon Cho²; So Young Kang²

¹Departments of Pathology, Hallym University Sacred Heart Hospital; ²Departments of Pathology, Samsung Medical Center

Gliomatosis cerebri (GC) is a diffuse neoplastic glial cell tumor infiltrating at least three lobes of brain and preserving the local parenchymal architecture. The entity of GC was deleted from the 2016 WHO classification of the CNS tumors. However, GCs still remain curious in both phenotype and genotype. This study is to stratify GCs into molecular categorization on the basis of genetic parameters of new integrated diagnosis and to investigate whether this molecular classification provide specific information.

Methods: We performed direct sequencing and PNA‐mediated real‐time PCR clamping for IDH1/2 and FISH or LOH for 1p/19q codeletion, immunohistochemistry using 90 paraffin‐embedded tissues.

Results: IDH1 and ATRX mutations and 1p/19q codeletion were detected in 35/90 patients (38.9%), 23/83 patients (27.7%), and 4/90 patients (4.4%). 90 GCs were subcategorized into astrocytic tumors (n=89) and oligodendroglial tumors (n=1). Among the 89 astrocytic tumors, 73.0% were IDH‐wildtype astrocytomas, grade II (n=27), III (n=35), and IV (n=3) and 27.0% were IDH‐mutant astrocytomas, grade II (n=9), III (n=13), and IV (n=2). There was a case of oligodendroglioma,IDH‐mutant&1p/19q‐codeleted (1.1%). There was no statistical difference between overall or progression‐free survivals and molecular subtypes within GCs. 30 patients showed disease progression during follow‐up. A half of these patients were diagnosed with glioblastoma at second biopsy and they were initially IDH‐wildtype (n=13) or IDH‐mutant tumors (n=2).

Conclusion: GCs largely comprised IDH‐wildtype astrocytic tumors as a genotype, and the majority of these tumors progressed to glioblastoma, IDH‐wildtype. New classification could not make it perfectly possible to stratify GC into prognostic relevant categorization.

P1‐94

Gliosarcoma in the IDH era: Imaging characteristics of 25 patients with correlative immunostaining

Joshua Klonoski; Cheryl Palmer; Miriam Peckham; Karen Salzman; Anne Osborn

Department of Pathology, University of Utah

Background: In the 2016 World Health Organizations Classification of Tumors of the Central Nervous System, gliosarcoma (GSC) is considered a variant of IDH‐wild type glioblastoma (GBM) characterized by a biphasic pattern with alternating areas exhibiting glial and mesenchymal differentiation. GSC can be primary or radiation‐induced and is an intra‐axial brain lesion which often abuts a dural surface. While some GSC have indistinguishable imaging characteristics from glioblastoma, aggressive lesions can erode through the dura and skull and involve the extra‐cranial soft tissues. We present the largest known imaging series of GSC with immunohistochemical and histologic correlation, documenting them as IDH(‐) and delineating their imaging spectrum.

Methods: Pathology proved GSC cases were collected from our quaternary care center spanning the last 16 years. IDH status was either documented or obtained by staining tissue blocks. When available, p53, PTEN, MIB‐1, EGFR amplification status, and MGMT methylation status were recorded and imaging findings tabulated.

Results: 25 cases were identified, 21 were de novo, and 4 were radiation‐induced. All lesions contacted a dural or pial surface. All cases were negative for an IDH R132H mutation, including post‐radiation GSC. 16/16 cases showed non‐amplification of EGFR/CEP7. MGMT methylation was present in 2/17. Imaging features included areas of nodular thickening in necrotic lesions which appeared to abut the site of pial or dural contact.

Conclusion: We present the largest reported imaging collection of GSC cases with correlative molecular and histologic testing.

Oral 3: O3‐1

Expression of GPR17, a negative regulator of oligodendrocyte differentiation and maturation, in Nasu‐Hakola disease brains

Jun‐ichi Satoh¹; Yoshihiro Kino¹; Tsuyoshi Ishida²; Yuko Saito³

¹Department of Bioinformatics and Moleccular Neuropathology, Meiji Pharmaceutical University: ²Department of Pathology and Laboratory Medicine, Kohnodai Hospital, NCGM; ³Department of Laboratory Medicine, National Center Hospital, NCNP

The G protein‐coupled receptor 17 (GPR17), a Gi‐coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of NG2+ preoligodendrocytes into O4+ premyelinating oligodendrocytes, whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu‐Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss‐of‐function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and activation of microglia predominantly in the white matter of frontal and temporal lobes. Although GPR17 is a key regulator of oligodendrogenesis, a pathological role of GPR17 in NHD brains with relevance to development of leukoencephalopathy remains unknown. We studied the expression of GPR17 in five NHD brains and eight control brains by immunohistochemistry. We identified GPR17‐immunoreactive premyelinating oligodendrocytes with a multipolar ramified morphology distributed in the white matter and the grey matter of all cases examined. However, we did not found statistically significant differences in the number of GPR17‐expressing cells between NHD and control brains both in the white matter and the grey matter due to great variability from case to case. These observations do not support the view that GPR17‐positive premyelinating oligodendrocytes play a central role in the development of leukoencephalopathy in NHD brains.

O3‐2

Neuropathology of SOD1‐ linked familial ALS with marked intrafamilial phenotypic variation

Shinji Ohara¹; Yo‐ichi Takei¹; Akinori Nakamura¹; Kenya Oguchi¹; Akiyo Hineno²; Yoshiaki Furukawa³

¹Department of Neurology, Matsumoto Medical Center; ²Department of Neurology, Shinshu University School of Medicine; ³Department of Chemistry, Keio University

Introduction: Familial ALS with a mutation in the superoxide dismutase (SOD1) gene often shows marked intrafamilial phenotypic variation, although its pathologic background remains to be investigated.

Methods: Immunohisto‐ and immunochemical studies using the SOD1 oligomer antibody were performed on postmortem brain and spinal cord from three patients (two brothers and a son) with C111Y mutation in SOD1 gene. The patients came from a family in which the rate of progression of the illness varied markedly over three generations. Two of them (father and son) presented with an ALS phenotype and both died at age 53, 1.2 and 4 years after the onset. One patient with a spinal muscular atrophy (SMA) phenotype died at age of 89 more than 50 years after the onset of his disease.

Results: The severity and the distribution of the lesions are different among patients, reflecting their clinical features. Loss of lower motor neurons was demonstrable in all patients, although only by quantitatively in the patient with SMA phenotype with the longest survival. Pathological oligomers could be detected immunohistochemically in all patients and immunochemically in the anterior horn of frozen tissues in two patients including SMA phenotype.

Conclusions: Despite the marked phenotypic difference, pathological oligomers could be found in all patients immunohisto‐ and/or immunochemically, suggesting the presence of acquired factor(s) to modify SOD1 misfolding processes.

O3‐3

Excessive soluble iron stimulates microglia to release glutamate in ALS spinal cords

Noriyuki Shibata¹; Motoko Niida‐Kawaguchi¹; Kenta Masui¹; Akiyoshi Kakita²; Kazuhiko Watabe³

¹Department of Pathology, Faculty of Medicine, Tokyo Women's Medical University; ²Department of Pathology, Brain Institute, Niigata University; ³Department of Medical Technology, Faculty of Health Sciences, Kyorin University

Introduction: Previous studies have demonstrated increased iron and glutamate levels in the spinal cord of amyotrophic lateral sclerosis (ALS). The present study aimed to clarify the relationship between these two substances.

Methods: Immunohistochemical and immunoblot analyses were carried out on spinal cords at autopsy from 10 sporadic ALS patients and 10 age‐matched control subjects. A mouse microglial cell line (BV‐2) was used for cell culture experiments.

Results: Ferritin (Ft), aconitase 1 (ACO1), TNFα‐converting enzyme (TACE), and glutaminase C (GAC) were mainly expressed in ALS activated microglia. Total protein‐normalized intracellular soluble iron content and β‐actin‐normalized Ft optical density on immunoblots were significantly increased in the ALS group as compared to the control group. Ferroportin (FPN) expression levels were significantly reduced in the ALS groups as compared to the control group. Ferric ammonium citrate (FAC) let BV‐2 cells increase intracellular soluble iron content and Ft expression levels. FAC also let BV‐2 cells release glutamate and TNFα, and these increases were cancelled by pretreatment with inhibitors for ACO1 and TACE, respectively. TNFα let BV‐2 cells release glutamate, and the increase was cancelled by pretreatment with GAC inhibitor. The TNFα‐released hepcidin let BV‐2 cells reduce intracellular FRP expression levels.

Conclusion: Our results provide in vivo and in vitro evidence that increased soluble iron levels stimulate microglia to release glutamate in ALS spinal cords via ACO1, TACE and GAC. Additionally, it is likely that a mechanism by which intracellular soluble iron levels are maintained in microglia may be underlined in ALS.

Symposium 4: S4‐1

Muscle pathology in the era of NGS

Ichizo Nishino

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry

Next generation sequencing (NGS) is a powerful technique that allows us to screen theoretically all genes for mutations at one time. Nevertheless, the definitive diagnosis is made only around 30% of cases – it is sometimes called “30% issue”. The main reason for this relatively low diagnostic rate, in addition to technical limitations of NGS itself, is the fact that NGS does not simply tell the mutation(s) but provides a long list of variants – nucleotides different from the reference sequence. Among all those variants, mutation candidates need to be chosen based upon likely inheritance pattern, the features of the disease and often with the help of prediction software. Furthermore, even with a strong candidate, laborious functional assays are usually necessary to validate its pathogenicity.

In contrast, if the mutations whose pathogenicity has already been well established are included in the list of variants that NGS produces, theoretically, the diagnosis can be almost immediately. In fact, most of the “30%” whose diagnosis is successfully made have known mutations, clearly indicating the necessity of enriching genotype‐phenotype correlation data for various genetic disorders.

In this line, precise phenotyping will be more important than before for successful NGS analysis. Without correct phenotype information, NGS analysis and result will be misinterpreted. Historically, most muscle diseases have been classified and/or defined by pathological features in addition to clinical features, but the disease definition will most likely be more gene‐ or mutation‐based in the near future. In this transition period, we must establish detailed genotype‐pathological phenotype correlation, for which muscle pathology should play a major role.

S4‐2

The road less traveled: the evolving role of morphological assessment in the era of precision medicine ‐ through a window of mitochondrial myopathy

Kurenai Tanji

Department of Pathology & Cell Biology, Columbia University

This is a dynamic phase in the history of mitochondrial medicine. The increasing utility of genetic information in the diagnosis of myopathies, owing to the rapidly advancing next generation sequencing, is transforming the role of conventional tissue diagnosis. Morphological categorization remains essential for many myopathies, especially when genetic abnormalities of unknown significance might complicate a diagnostic odyssey. However, a morphological assessment must consider the specific genetic abnormality. Furthermore, morphology must take into account the clinical stage of the disease, since myopathies are increasingly degenerative at large, and the pathology can change dramatically as the disease progresses. Mitochondrial disease is one of the systemic or neurological conditions in which genetic‐pathological correlation has long played a critical role in diagnosis and patient care. With the ever‐increasing accessibility to high throughput genetic sequencing, the categories of this bioenergetic disease have been expanding at an unprecedented speed, and have led to a number of therapeutic approaches. For example, deoxynucleotide substrate enhancement therapy is being used for mitochondrial DNA (mtDNA) multiple deletions/depletion syndrome associated with thymidine kinase 2 gene (TK2) mutations. Against this background of rapid diagnostic changes, this presentation aims to highlight: 1. A brief history of muscle biopsy in mtDNA multiple deletions/depletion syndrome; 2. The evolving role of morphological assessment ‐ from bedside to bench and back; 3. A novel imaging technology, cryo‐electron tomography, and its potential value in the era of precision (accurate) mitochondrial medicine.

S4‐3

Muscle pathological changes of cancer associated myositis

Jun Shimizu

Department of Neurology, Graduate School of Medicine, The University of Tokyo

Idiopathic inflammatory myopathies (IIMs), also known as myositis, are a group of acquired, heterogeneous, autoimmune diseases that are classified into polymyositis (PM), dermatomyositis (DM), immune‐mediated necrotizing myopathy (IMNM) and non‐specific myositis based on clinical features and pathological findings. As a clinical phenotype, cancer association in myositis has been known from long ago. Since the first description of the cancer association in a DM patient in 1916, the association of cancers in DM patients has been extensively reported in the medical literature. Historically, cases of paraneoplastic necrotizing myopathies have been also reported from 1960s. Currently, more than 15 myositis‐specific autoantibodies (MSAs) have been identified. Because a number of MSAs correlate with specific clinical features of patients with IIMs, and only one of MSAs is detected in individual patients, it is presumed that autoantibodies or their target molecules correlate with underlying pathomechanisms of IIMs. With regard to MSAs associated cancers, it is well‐known that adult patients with DM who carry anti‐transcriptional intermediary factor (TIF1) γ are more likely to develop malignancy than anti‐TIF1γ negative patients. Besides anti‐TIF1γ antibodies, a few studies have indicated the increased cancer risk in adult patients with anti‐NXP2, anti‐SAE, and anti‐HMGCR antibodies. In this session, we will talk about our studied on the clinical and pathological features of cancer associated myositis (CAM), focusing on CAM with anti‐ TIF1γ and anti‐HMGCR antibodies.

Symposium 5: S5‐1

Interaction between cerebrovascular disease and Alzheimer pathology

Masafumi Ihara

Department of Neurology, National Cerebral and Cardiovascular Cetner

Epidemiological investigations have proposed strict control of vascular risk factors as a strategy to overcome dementia, because of the close interaction between cerebrovascular disease (CVD) and Alzheimer's disease. In light of recent advances in basic, translational, and clinical research in the area, I would like to focus on the significance of CVD in Alzheimer's disease pathogenesis. Alzheimer's disease and CVD share several risk factors, and the coexistence of both pathologies is frequently noted. CVD and subsequent cerebral blood flow reduction would increase amyloid β (Aβ) production by modulating &beta; and γ‐secretase. Furthermore, CVD impairs Aβ clearance, which is mainly driven by vascular mediated systems, including active transport across the blood‐brain barrier, and perivascular lymphatic or paravascular glymphatic drainage systems. Thus, CVD may disturb homeostasis between Aβ production and clearance, thereby aggravating Alzheimer's disease. Recent translational researches in this field aim to facilitate Aβ clearance. Several candidate drugs are being tested in clinical trials such as our trial using cilostazol for MCI (COMCID study). Compared with Aβ pathology, little is known about the relationship between tau pathology and CVD, although some studies have shown that CVD has an influence on tau pathology. The close interrelationship between Alzheimer's disease and CVD suggests the necessity of the maintenance of cerebrovascular integrity, which may herald a new generation of dementia treatment strategies.

S5‐2

The Gliovascular Unit in White Matter Disease associated with Post‐Stroke and Vascular Dementias

Raj Kalaria

Institute of Neuroscience, Newcastle University Graduate School of Medicine

Introduction: Diffuse white matter (WM) changes are described in cerebral small vessel diseases (SVD). We previously showed disruption of the gliovascular unit is associated with breach of the blood‐brain barrier (BBB) in frontal WM disease. Besides astrocytes, the gliovascular unit also incorporates pericytes but their status is unclear in vascular dementias.

Methods: We assessed post‐mortem brains from prospectively assessed non‐demented (PSND) and demented (PSD) stroke survivors, vascular dementia (VaD) subjects and normal ageing controls. Immunohistochemical and immunofluorescent staining methods were used to study the localisation, distribution and quantification of astrocytes and pericytes identified by glial acidic fibrillary protein (GFAP), collagen 4 (COL4) and platelet derived growth factor receptor‐beta (PDGFR‐beta) immunoreactive profiles of capillaries in the WM and grey matter.

Results: COL4 and PDGFR‐beta reactive pericytes adopted typical crescent morphology wrapped closely around capillary walls, readily evident in cross‐sections. We estimated pericyte numbers per percent COL4 immunoreactive area and per mm vessel length in the frontal WM in ageing controls were 1.6 and 1.7, respectively. Whilst these numbers in controls were not altered in comparison to post‐stroke non‐demented subjects they were reduced by 30 percent in PSD and VaD subjects (P equal 0.001).

Conclusions: Our results show decreased expression of COL4‐positive pericytes in capillaries in the frontal WM of subjects with PSD and VaD. More profoundly, our findings suggest that down regulation of pericyte‐like cells is associated with loss of control of the microcirculation within the deep WM in cerebral SVD and dementia associated with cerebrovascular disease.

S5‐3

Role of small vessel disease in the boundaries of large vessel disease and Alzheimer disease

Hidekazu Tomimoto

Department of Neurology, Mie University Graduate School of Medicine

Small vessel disease (SVD) encompasses vascular abnormalities in the vessels of various sizes ranging from small arteries to post capillary venules and small veins. The pathologic process in this size of vessels are mainly attributable to two etiologies; ie, hypertensive SVD and cerebral amyloid angiopathy (CAA) . This presentation focuses on the boundary field between SVD and large vessel disease and those between SVD and Alzheimer dementia. First, large vessel disease may lead to small vascular lesions and may masquerade SVD such as granular cortical atrophy which is caused by microembolism and hypoperfsion in the border zone territory of the cerebral cortex. With advancement of MRI technologies, these small lesions are getting visible and should be paid attention not to be confused with SVD. Cortical microinfarctions are observed in high prevalence after transcatheter manipulation of heart and cerebral vessels and may remain visible or are transformed to embolic microbleeds after a long duration. Second, CAA may cause characteristic vascular lesions including subcortical hemorrhage, cortical superficial siderosis, strictly‐lobar microbleeds and cortical microinfarctions. In the absence of Alzheimer pathology of the neuropil, CAA may be classified to a type of vascular dementia and postulated to be a link of overlapping pathology between vascular dementia and Alzheimer disease.

S5‐4

Exploring the pathologic targets in a white matter ischemic stroke model based on somatotopic mapping of the pyramidal tract

Min‐Cheol Lee^1,2; Kyung‐Wha Lee¹; Hyoung‐Ihl Kim²

¹Department of Pathology, Chonnam National University Medical School; ²Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology

Background: Recent meta‐analysis revealed that ischemic strokes are highly associated with white matter (WM) lesions, however, a few studies have investigated due to the difficulty in generating animal models of WM stroke.

Method: We created a highly reproducible rat model of internal capsule (IC)‐specific stroke using a photothrombotic technique based on anterograde somatotopic mapping of motor fibers, and studied neurologic behaviors, metabolic changes by PET analysis, comprehensive histopathology including ultrastructure, molecular pathogenesis and some therapeutic trials.

Result: WM pathologies result in motor dysfunction. Motor function recovery was correlated to the extent of IC injury proper rather than the infarct volume. Pathologic changes indicate that WM is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Longitudinal PET results showed that capsular infarct resulted in a persistent decrease in brain metabolism in remote areas from ischemic lesion; diaschisis, and contributes to manifest the malfunctions of lesion‐specific functional connectivity. The lesion of diaschisis revealed characteristic histopathology and electron microscopy, and molecular events.

Conclusion: As the pathology of white matter stroke revolves around disrupted connectivity and injured axons and glial cells, the mechanisms of WM ischemic injury and the regenerative responses of glial cells and their signaling pathways are differ significantly from those in grey matter. Exploring the relationship between histopathology and metabolic changes by PET in the subcortical infarct model, the development of diaschisis, is a critical target to understand the underlying mechanisms leading to the progression of neurologic outcomes and the development of effective therapies.

Oral 4: O4‐1

Stereoscopic inspection of autopsied brain reconstructed from two‐dimensional images

Hiroshi Shintaku^1,2,3; Mari Yamaguchi⁴; Shuta Toru⁵; Masanobu Kitagawa⁶; Katsuiku Hirokawa⁷; Takanori Yokota³; Toshiki Uchihara^1,2,3

¹Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science; ²Neuromorphomics, Nitobe‐Memorial Nakano General Hospital; ³Dept. of neurology and neurological science, Tokyo Medical and Dental University; ⁴Media technology Laboratory, Tokyo Metropolitan Institute of Medical Science; ⁵Dept. of neurology, Nitobe Memorial Nakano General Hospital; ⁶Dept. of comprehensive pathology, Tokyo Medical and Dental University; ⁷Dept. of pathology, Nitobe Memorial Nakano General Hospital

Introduction: Macroscopic inspection of autopsied brain constitutes a connection between clinical manifestations and microscopic findings.Clinical image such as CT and MRI are 3‐dimensionalized,while macroscopic countepart of the autopsie brains are usually presented on 2 dimensional basis.This is the first trial to overcome this gap by creating a 3‐dimensional surface model of autopsied brains.

Materials and methods: Cerebral hemispheres from five autopsied brains (normal, progressive supranuclear palsy, dementia with Lewy bodies, amyotrophic lateral sclerosis and Alzheimer disease), routinely fixed in formalin were photographed from multiple directions at about 30 degrees intervals using digital single‐lens reflex camera. These 2‐dimensional images were put into a software Autodesk ReCap Pro cloud service(http://www.autodesk.co.jp/products/recap/overview) to reconstruct a 3‐dimensional surface model.

Result: Reconstruction of 3‐dimensional surface model of the brain hemisphere was successful from 60 to 80 images. It is now possible to observe gross or regional atrophy at whatever scale from whatever magnifications, and detect characteristic findings of disease.

Conclusion: This is the first report that successfully established a 3‐dimensional surface model reconstruction method of human autopsied brains. There is still room for improvement regarding standardizing image acquisition (lighting, angle, stabilization of the whole brain) and data processing. By using this 3‐dimensional overview, it is now possible to more accurately identify the relationship between the brain surface and microscopic findings and clinical findings including imagery. Furthermore, these reconstructed datasets may be useful for quantification of atrophy that may represent disease‐specific patterns.

O4‐2

Hippocampal adult neurogenesis is perturbed in microcephaly model mice with aging

Hisashi Takahashi¹; Akira Fujimori²; So Tando¹; Miyuki Mori¹; Takeshi Yaoi¹; Takahiro Fujimoto¹; Kyoko Itoh¹

¹Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine; ²Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences

Introduction: Autosomal recessive primary microcephaly‐5 (MCPH5) in human is caused by the mutation of the abnormal spindle‐like, microcephaly‐associated (ASPM) gene. The aim of our study is to elucidate the role of ASPM in the hippocampal adult neurogenesis with aging by immunohistochemistry and morphometry.

Methods: We prepared CAG‐mediated Cre‐loxP conditional ASPM ortholog (Aspm) knockout (KO) and WT mice of both sexes at postnatal 10‐20 weeks, 40‐50weeks, 60‐70weeks and 100‐110 weeks. Mice received six bolus administration of BrdU (50 mg/kg; i.p.) every 12 hours and were sacrificed 24 hours after the last injection. Fixed brains were embedded in paraffin and immunostained for BrdU as well as neuronal lineage markers, such as doublecortin and nestin. We evaluated the hippocampal volume and the number of BrdU‐, doublecortin‐ and nestin‐positive cells in the dentate gyrus of the hippocampus in both genotypes and sexes.

Results: Total volume of hippocampus and dentate gyrus was significantly smaller in Aspm KO mice compared to WT mice at any age, although there was no tendency of age‐dependent reduction in volume. The number of BrdU‐positive cells in the dentate gyrus showed a decrease with age in both genotypes; however, the reduction was significant in Aspm KO mice as compared to WT mice at any age.

Conclusion: These data suggested that Aspm might contribute to the proliferation of hippocampal new‐born cells in adult mice, although further investigation is needed to verify molecular pathomechanisms.

O4‐3

Presumptive function of microcephaly related gene Aspm during murine brain development

Madoka Tonosaki¹; Akira Fujimori²; Takeshi Yaoi¹; Kyoko Itoh¹

¹Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine; ²Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences

Introduction: The mutation of ASPM (abnormal spindle‐like microcephaly associated) causes primary autosomal recessive microcephaly in human. In order to evaluate the pathomechanisms of abnormal brain development, we performed histometric analyses using mice model.

Methods: Brain specific Aspm knockout mice (NesCre; Aspm ^f/f, Aspm cKO) were generated and the phenotype of the embryonic brains was examined. The brains were removed at embryonic day 12.5 (E12.5), E14.5 and E16.5, fixed with 4% PFA and the cryosections were stained with the following primary antibodies and labeling kit.; Tbr1, Ctip2 and Satb2 (for studying layer formation), pHH3, BrdU and EdU (for analyzing proliferation), CC3 and TUNEL (for detecting apoptosis). For neurogenesis, birthdating analysis using EdU was conducted. The brains were collected 2 days after EdU administration into pregnant mice (E12.5 or E14.5). The images were obtained with confocal laser microscope and analyzed using ImageJ.

Results: A deficiency of Aspm resulted in a reduction of cerebral wall thickness at a late neurogenesis (E16.5) during murine corticogenesis. Proliferation index evaluated by pHH3 and BrdU labeling did not show apparent changes at all stages analyzed. Neurogenesis index examined by EdU labeling reduced only at the later stage (E16.5). In contrast, a significant increase in apoptosis was found in the cerebral wall of Aspm cKO from early stage (E12.5) to late stage (E16.5) of neurogenesis.

Conclusion: Our findings suggested that a high occurrence rate of apoptosis during corticogenesis might be one of the underlying mechanisms of microcephaly due to deficiency of Aspm.

O4‐4

Epoch‐making therapy that delays ALS progression in G1H‐G93A ALS mice: oral administration of non‐purine‐analogue xanthine oxidoreductase inhibitors (XORIs)

Shinsuke Kato¹; Masako Kato²; Masahiro Ii¹; Hiroshi Kohama¹; Kosuke Yonekura¹; Yuki Kaida¹; Keiko Kato¹; Kiyota Kato³; Takeshi Nishino⁴

¹Division of Neuropathology, Tottori University Faculty of Medicine; ²Division of Molecular Pathology, Tottori University Faculty of Medicine; ³School of Medicine, Hiroshima University; ⁴University of Tokyo Health Sciences

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease. The only universal drug currently available to treat ALS is the glutamate antagonist riluzole.

Methods: With respect to three non‐purine‐analogue (np)‐XORIs, we used TEI‐6720 (Febuxostat), Y‐700 and FXY‐051 (Topiroxostat), and purine‐analogue Allopurinol was also used. As a placebo, methylcellulose (drug solvent) was given. We orally administered four XORIs and placebo to G1H‐G93A mice carrying human mutant G93A‐SOD1 (25 copies) or littermates. As for clinical evaluation, XORIs and placebo were administered at following two points: 80 days of age (preclinical stage) and at the ALS onset. The five exercise testing was conducted: extension reflex, inclined plane, footprint, rotarod, and beam balance tests. Concerning neuropathological studies, XORIs and placebo were administered from 80 to 115 days of age to G1H‐G93A mice or littermates.

Results: All np‐XORIs significantly delayed disease onset, prolonged survival and the duration of disease stages, improved ALS symptoms, and alleviated weight loss. All exercise testing showed the significantly‐improved motor function in G1H‐G93A mice treated with np‐XORIs. Significant amelioration of disease was seen even when np‐XORIs were administered after the ALS onset. Histopathological quantitative evaluation at 115 days revealed that G1H‐G93A mice treated with np‐XORIs had well‐preserved motor neurons and fewer inclusion bodies, compared with mice treated with Allopurinol or placebo. Regarding clinical and pathological results, Allopurinol was the same as placebo.

Conclusion: Our results indicate that np‐XORIs could apply to oral therapy of human ALS patients.

Symposium 6: S6‐1

Molecular heterogeneity in IDH‐mutant gliomas

Michael E Buckland^1,2

¹Neuropathology Department, RPA Hospital, Sydney, Australia; ²Brain & Mind Centre, University of Sydney, Sydney, Australia

The current WHO classification recommends that diffuse gliomas, including those with mixed (oligoastrocytoma) or ambiguous histological features, should be classified as either astrocytoma or oligodendroglioma based on key molecular alterations (e.g. IDH mutation status, ATRX immunohistochemistry and 1/19q codeletion status). However there have been several reports of diffuse gliomas showing evidence of genetically distinct oligodendroglial and astrocytic cell populations. While seemingly rare, the true incidence of these ‘dual‐genotype’ gliomas is difficult to ascertain. We have examined over 70 IDH‐mutant gliomas, originally reported to have either a mixture of two distinct neoplastic cell types (astrocytic, oligodendroglial), or morphological phenotypes ambiguous between these two lineages. All tumours underwent central histological review and IDH1(R132H)/ATRX dual staining. Further molecular analyses were then performed which included 1p/19q FISH and/or CHG‐array, quantitative pyrosequencing and a targeted glioma deep next generation sequencing panel. Our findings confirm that dual‐genotype ‘oligoastrocytomas’ are a rare but real phenomenon, and may provide insights into early stages of gliomagenesis.

S6‐2

CNS high‐grade neuroepithelial tumor with BCOR internal tandem duplication

Sumihito Nobusawa

Department of Human Pathology, Gunma University Graduate School of Medicine

A recent study of tumors previously institutionally diagnosed as so‐called CNS primitive neuroectodermal tumors revealed four new distinct entities defined by novel genetic alterations, including CNS high‐grade neuroepithelial tumors with BCOR alteration (CNS HGNET‐BCOR), characterized by somatic internal tandem duplication within exon 15 of BCOR (BCOR ITD). BCOR‐ITD has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD‐positive tumors have been reported to share similar pathological features. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET‐BCOR exhibited glial cell morphology, ependymoma‐like perivascular pseudorosettes, and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S‐100 protein, and synaptophysin were observed in CNS HGNET‐BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET‐BCOR, CCSK, and URCS/PMMTI may constitute a group of BCOR ITD‐positive tumors, only CNS HGNET‐BCOR has histological features suggestive of glial differentiation. CNS HGNET‐BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.

S6‐3

Histological and molecular genetic features of epithelioid glioblastoma

Hideaki Yokoo

Department of Human Pathology, Gunma University

Epithelioid glioblastoma (E‐GBM) is a rare aggressive variant of IDH‐wildtype glioblastoma newly incorporated in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm, devoid of stellate cytoplasmic processes. Earlier studies uncovered that approximately 50% of E‐GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E‐GBM are recognized as primary/de novo lesions; however, several E‐GBM with co‐ or pre‐existing lower‐grade lesions have been reported. We collected 14 cases of E‐GBM with (10) or without (4) lower‐grade lesions, and molecular analyses demonstrated that the prevalence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions in E‐GBM were 13/14 (93%), 10/14 (71%) and 11/14 (79%), respectively, and concurrent BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions were observed in 7/14 (50%) of E‐GBM. These alterations were also frequently seen in the lower‐grade lesions irrespective of the histology. Genetic analysis including array comparative genomic hybridization performed for 5 E‐GBM with co‐ and pre‐existing lower‐grade components revealed that all molecular changes found in the lower‐grade components were also observed in the E‐GBM components, and additional changes were detected in the E‐GBM components. The lower‐grade components may be distinct infiltrative components of E‐GBM, reflecting intratumoral heterogeneity, or a precursor of E‐GBM.

S6‐4

Pilomyxoid Astrocytoma: What do we know about the tumor?

Tarik Tihan

Department of Pathology, University of California, San Francisco (UCSF)

Pilomyxoid Astrocytoma (PMA) was reported originally in 1999 as a piloid neoplasm with distinct features including monomorphic bipolar cells, myxoid matrix and an angiocentric pattern. The tumors occurred almost exclusively in the hypothalamic region and in young children, and the prognosis was worse than pilocytic astrocytoma (PA) in the same location and age group. PMA often had higher rate of recurrence and cerebrospinal seeding compared to PA, but still better than diffuse gliomas. Subsequently, examples were reported in the spinal cord and cerebrum, and some case reports were published suggesting that pilomyxoid astrocytomas occurred in adults as well as in odd locations. However, many such cases fail to demonstrate the diagnostic criteria, and probably qualify as tumors other than PMA. In 2008, a tandem duplication producing an oncogenic BRAF fusion was discovered in PA and some PMAs. The MAPK pathway alterations are now considered typical of both PA and PMA, and tumors that do not harbor genetic alterations in this pathway often belong to other entities. In summary, PMA is a tumor in the pilocytic category and typically occurs in young children in the hypothalamic/chiasmatic region and show monomorphous histological characteristics. There is clear evidence in the literature that PMAs have a higher rate of recurrence and cerebrospinal spread compared to PMA even after matching for age and location. It is important to be judicious in using diagnostic criteria, and remember that tumors with only focal pilomyxoid features probably do not belong to this group.

Oral 5: O5‐1

Spectrum of central nervous system tumors in infants according to 2016 WHO Classification from a tertiary care centre in India

Kavneet Kaur; Vaishali Suri; Mehar Chand Sharma; Ajay Garg; Ashish Suri; Chitra Sarkar

All India Institute of Medical Sciences (AIIMS), New Delhi

Introduction: Central Nervous System(CNS) tumors in infants (< 3 years‐of‐age) are rare and form a distinct subset of pediatric CNS tumors.These tumors differ from tumors in older children with respect to clinical profile, histology, management and tend to have poorer outcome.

Objectives: a)To analyze the spectrum of all CNS tumors diagnosed in infants;b)To recategorize them according to 2016 WHO classification, wherever possible;c)Compare the statistics with the available literature.

Methods: All cases diagnosed over the last 14 years(2002‐2016) were retrieved from the archives of Department of Pathology,AIIMS, New Delhi.

Results: A total of 378 cases were identified(2.7% of total CNS tumors). The tumors were equally distributed across supratentorial and infratentorial compartments followed by spinal cord. Nearly 38% tumors were diagnosed in infants < 1year‐of‐age. Male preponderance (M:F=2.2:1)was noted. Almost one‐fourth were astrocytic tumors comprising mainly of Grade I pilocytic astrocytoms (62%). Glioblastomas (17%) and Grade II/III diffuse astrocytomas (17%) were less common. Embryonal tumors(13.5%) (Medulloblastoma‐36,AT/RT‐9,ETMR‐2,NOS‐4), ependymomas (8.7%) (GradeIII‐24, GradeII‐9), germ‐cell‐tumors (5%), craniopharyngiomas(4%), choroid plexus tumors (3.2%), meningiomas(3.2%), schwannomas(3%), glioneuronal(2.3%), and few cases each of hemangioblastoma, lymphoma, pineoblastoma and oligodendroglioma were seen. Among malignant tumors, medulloblastoma were the most‐common, followed by anaplastic ependymomas and glioblastomas.

Conclusions: The spectrum of infantile brain‐tumors in our institution is largely similar to world‐wide data with astrocytomas being the most common. However, one study published from South‐India found choroid plexus tumors,while another from the far‐east found medulloblastomas to be the most‐common. Larger multi‐institutional studies are warranted to analyse racial and molecular differences from their childhood and adult counterparts.

O5‐2

Unusually high frequency of dual/ double pathology in neurocysticercosis causing drug resistant epilepsy in India. Chance association or causal?

Radhika Kailas Mhatre¹; Anita Mahadevan¹; Rajalakshmi P¹; Arivazhagan A²; Sanjib Sinha³; Mundlamuri Ravindranadh Chowdary³; Rose Dawn Bharath⁴; Raghavendra Kenchaiah³; J Saini⁴; M Bhaskar Rao²; P Satishchandra³; Shankar SK¹

¹Department of Neuropathology, NIMHANS, Bangalore, India; ²Department of Neurosurgery, NIMHANS, Bangalore, India; ³Department of Neurology, NIMHANS, Bangalore, India; ⁴Department of Neuroimaging and Interventional Radiology, NIMHANS, Bangalore, India

Introduction: Neurocysticercosis(NCC) as cause of drug resistant epilepsy(DRE) is more commonly reported from India (0.06%). We review the neuropathological findings in patients undergoing resective surgery for DRE due to NCC.

Methods: Histologically confirmed cases of NCC causing DRE in patients undergoing resective surgeries between 2004‐2018 in NIMHANS, India were collected. Clinical, demographic and neuropathological findings were reviewed. Histological alterations in adjacent tissues were evaluated using NeuN, GFAP, phosphorylated neurofilament, vimentin, CD34 for glial/neuronal alterations and Masson trichrome, and Luxol Fast blue for evidence of fibrosis/demyelination to determine cause of epileptogenesis of these lesions.

Results: There were 13 cases of NCC causing DRE, constituting 0.037%[13/346]. [Age range:17‐35yrs, Male:Female=1.1:1]. Seizure duration ranged from 3‐20yrs, with seizure onset between 5‐27yrs. On MRI, lesions were T1 hyperintense and T2 isointense with blooming on GRE, and CT showed calcification in 11/13. All had single cysticercal lesion and involved hippocampus(7/13), temporal(2/13), frontal(2/13), parietal(1/13), amygdala(1/13). On histopathology, cysts were degenerated(6/13) or fibrocalcific(7/13) stage. Adjacent cortex revealed fibrosis(9/13), inflammation(4/13), gliosis(4/13), axonal disruption/beading(2/13), and variable synaptic/neuronal dysmorphic changes. Vascularization was uncommon. Associated epileptogenic lesions were identified in 10/13 [76.9%], Hippocampal sclerosis(HS) Type 1(8/10), Focal cortical dysplasia(FCD) 1B(1/10), FCD 2B(1/10). Dentate gyrus revealed thinning, gaps or duplication(5/8). Surgical outcome available in 2 [Engel Ia and Ib].

Conclusion: Associated HS (Dual pathology) was common in majority (61.5%) suggesting that HS is a secondary/epiphenomenon. Perilesional changes such as inflammation, gliosis, dystrophic synaptic and axonal pathology play a role in inducing epilepsy. Association of FCD suggests that these may not always be developmental.

O5‐3

Using models of cell‐cell interactions in the focal cortical dysplasia (FCD) to unravel the cellular diversity in developmental cortical lesions

Yao‐Feng Li¹; Fatma Sceirf¹; Simon Raphael Picker¹; Martin Tisdall²; Jessica Jessica^1,2; Helen Cross²; Aime Avery²; Francois Guillmot³; Darren Hargrave^1,2; Thomas Jacques^1,2

¹UCL Great Ormond Street Institute of Child Health; ²Great Ormond Street Hospital for Children NHS Foundation Trust; ³The Francis Crick Institute

Introduction: Interactions between different cell types seem to be critical in developmental cortical lesions. However, methods to understand these interactions are limited. We have investigated cell‐cell interactions in FCD, one of the most common cortical lesions leading to multidrug‐resistance in paediatric epilepsy. We hypothesised that FCD contains multiple cells types and their interactions are important in explaining the pathogenesis.

Methods: Using gene expression analysis, we identified the major secretory molecules in balloon cell cortical dysplasia (FCDIIb and cortical tubers). Then, we characterised the cell types expressing these signalling molecules using immunohistochemistry. Finally, to explore the functional relevance, we have developed an organotypic slice culture model of FCD using tissue resected from epileptic surgery and visualised them using 3D technique CLARITY.

Results: Gene expression analysis identified 51 up‐regulated secretory proteins in balloon cell dysplasias compared to normal cortex or non‐balloon cell dysplasia. We performed immunohistochemistry for those that had the greatest differential expression and determined the identity of the expressing cells. Two of these markers were found in the distinct and unique cell populations, found mainly in the balloon cell dysplasias. In order to develop a functional model for cell‐cell interactions, we developed organotypic cultures from patients undergoing neurosurgery for epilepsy. We also demonstrate the alteration of these molecules in the FCD IIb case after treatment with an mTOR inhibitor.

Conclusion: We have identified novel cell‐cell signalling pathways and developed a model to determine the functional roles of these interactions. This provides a generalisable approach to understanding cellular heterogeneity in developmental disorders of the brain.

O5‐4

Galactosialidosis: clinicopathological features of four autopsied patients

Hiroshi Shimizu¹; Tanaka Hidetomo¹; Tani Takashi²; Ryoko Koike²; Isao Egawa³; Ryu Jokoji⁴; Jiro Idezuka⁵; Kiyomitsu Oyanag^6,7; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Brain Research Institute, Niigata University; ²Dept. of Neurol., Nishi‐Niigata Chuo Natl. Hosp; ³Dept. of Psychiatr., Nissay Hosp; ⁴Dept. of Pathol., Nissay Hosp; ⁵Dept. of Neurol., Ojiya Sakura Hosp; ⁶Div. of Neuropathol, Dept. of Brain Dis. Res., Shinshu Univ. Sch. of Med; ⁷Brain Res. Lab., Hatsuishi Hosp.

Introduction: Galactosialidosis (GS) is a rare autosomal‐recessive lysosomal storage disorder. The aim of the present study is to clarify the clinicopathological features of GS.

Methods: We examined four autopsied patients with GS, one with the late infantile (LI) type (Case 1, aged 13 years) and three with the juvenile/adult (J/A) type (Cases 2‐4, aged 51‐71 years). All had homozygous mutations in CTSA (IVS3 (Case 1) and IVS7 (Cases 2‐4)).

Results: All of the patients had visual disturbance, myoclonus, cerebellar ataxia, and gargoylism. Other symptoms included psychomotor retardation (Case 1) and pyramidal signs (Cases 1, 3, and 4). In the late stage of illness, cognitive regression/dementia (Cases 1, 3, and 4), muscle weakness (Case 3), and autonomic dysfunction (Case 3) were noted. Pathologically, all four cases showed neuronal swelling throughout almost the entire CNS, as well as in the peripheral autonomic ganglia, whereas neuron loss was limited to more restricted areas. The LI‐type patient showed severe neuronal loss in the motor cortex, thalamus, globus pallidus, and cerebellar molecular layer. In the J/A type, degenerative lesions were limited to the cerebellum and spinal ganglia in the youngest patient (Case 2), and then appeared to extend to the cerebral cortex, globus pallidus, Meynert nucleus, and spinal anterior horns in the older patients. Lewy bodies were commonly observed in the J/A subtype.

Conclusion: Patients with GS show diverse clinicopathological features depending on the subtype or location of the mutations. In the J/A subtype, age may influence the distribution of the degenerative lesions.

Symposium 7: S7‐1

Evaluation of glial biology in pathogenesis of CNS infections

Anita Mahadevan¹; Surya Tripathi¹; Keshava Prasad²; Shankar SK¹

¹Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS); ²Institute of Bioinformatics, Bangalore

CNS tuberculosis, Cryptococcal infection and cerebral toxoplasmosis are common AIDS associated opportunistic infections in developing countries. There is paucity of information on astroglial and microglial alterations in human brain following these infections as most studies focus on clinical, imaging, and laboratory diagnosis. In an autopsy study, we evaluated the pathomorphologic alterations with quantitative assessment of astroglia and microglia, with in prefrontal cortex and hippocampus in cases of tuberculous meningitis (TBM) and cryptococcal meningitis (CM) and cerebral toxoplasmosis to determine its possible contribution to long term neurological sequelae in survivors. Quantitative proteomics using iTraq labeling and mass spectrometric studies was performed to determine alterations in host at proteome level. Studies on neuronal‐astroglial interactions will provide insights into the neuropathogenetic mechanisms in the cellular and pathomorphological evolution to modulate the progress of these common opportunistic infections.

S7‐2

Neuroinvasion via peripheral nerves: Increasing evidence for its importance in viral encephalitis

Kum Thong Wong¹; Tzeh Long Fu¹; Kien Chai Ong²; Soon Hao Tan²

¹Department of Pathology, Faculty of Medicine, University of Malaya; ²Department of Biomedical Science, Faculty of Medicine, University of Malaya

Neuroinvasion by viruses is either via a haematogenous route or by neural pathways. The best known examples of neuroinvasion by neural pathways are the rabies virus via the peripheral nervous system and herpes simplex virus via the olfactory nerve. Among the enteroviruses, although poliovirus has been thought to enter the CNS via a haematogenous route following a viraemic phase, more recent evidence in transgenic mouse models strongly suggests retrograde axonal viral transmission in peripheral motor nerves. Among the other non‐polio neurotropic enteroviruses, Enterovirus A71, Coxsackievirus A16 and Enterovirus D68, there is also increasing clinical, brain MRI and autopsy evidence that strongly suggest the same retrograde axonal transmission is important for CNS invasion. Flaviviral encephalitides caused by Japanese encephalitis (JE) virus, Tick borne encephalitis virus and Murray valley encephaliltis often involve bilateral thalami in particular, apart from other CNS regions. We hypothesise that skin peripheral sensory nerve may be a portal for viral entry following an infected mosquito bite, and viruses could enter the CNS via estabished sensory pathways. In a footpad‐inoculation JE mouse model we found that the peripheral nerves, dorsal root ganglia (DRG) and thalami were preferentially infected early. Organotypic cultures of DRG also showed the cells supported viral replication. These findings support the involvement of sensory neural pathways in JE, and possibly other flaviviruses as well. If confirmed, neuroinvasion via the peripheral nervous system could be very important for further investigation to advance understanding of viral encephalitides

S7‐3

Neuropathology and neuropathogenesis of congenital Zika syndrome

Leila Chimelli^1,2

¹State Institute of Brain Paulo Niemeyer; ²Federal University of Rio de Janeiro

Zika virus, a flavivirus transmitted by Aedes aegypti, arrived and in Brazil in 2015. Infection varies from mild fever, arthralgia, rash, headache, myalgia, but may be asymptomatic. A major concern was the increased incidence of microcephaly with frequent calcifications in neonates born from mothers infected in the beginning of pregnancy. Intrauterine ultrasound/CT showed that cerebral maturation and growth were drastically affected. Many were born with arthrogryposis. Neuropathological lesions in neonates infected during pregnancy included three patterns of lesions, with a mixture of destruction, calcification, hypoplasia and migration disturbances. Hydrocephalus was severe in the first, due to midbrain damage and aqueduct obstruction. Small brains with mild/moderate (ex‐vacum) ventriculomegaly characterized the second pattern, both when infection occurred early. The third, with well‐formed brain and mild calcification, coincided with infection late in gestation. Absence of descending fibers resulted in hypoplastic basis pons, pyramids and cortico‐spinal tracts. Spinal motor cell loss explained the intrauterine akinesia, arthrogryposis and neurogenic muscle atrophy. The sensory system was normal. Viral detection in the germinal matrix and hemispheres confirmed infection and death of neural progenitors and glial cells, interfering with proliferation and migration. Topography and severity of lesions and timing of infection during gestation indicated a developmental vulnerability of the immature brain and explained the manifestations of the disease. Vascular occlusions in meninges and placenta do not discard a secondary ischemic process in the pathogenesis of destructive lesions. It is also possible that viral persistence, may be responsible for progression of lesions and symptoms observed after birth.

Evening Seminar 1: ES1‐1

Pentanucleotide repeat expansions in benign adult familial myoclonic epilepsy (BAFME)

Hiroyuki Ishiura

Department of Neurology, The University of Tokyo

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disorder characterized by infrequent generalized epilepsy and myoclonic tremor. The causative genes for BAFME have not been identified.

Fifty one families including 91 patients were enrolled in the study. We found conserved haplotypes among the families, which enabled us to narrow the candidate region to 134 kb. An intensive search of the whole genome sequence data revealed TTTCA and TTTTA repeat expansions in intron 4 of SAMD12, which were found exclusively in the patients in the 49 families. In a homozygous patient, mild and diffuse loss of Purkinje cells and halo‐like amorphous materials around the cytoplasm of several Purkinje cells were evident, whereas the feature was inconspicuous in patients with heterozygous mutations. RNA foci consisting of UUUCA repeats, but not of UUUUA repeats, were observed in neurons of the autopsied brains. No ubiquitinated inclusions were found in autopsied brains.

We hypothesized that the same repeat motifs in other genes might be involved in the remaining two families without repeat expansion mutations in SAMD12. We found accumulated short reads filled with TTTCA and TTTTA repeats, which led to identification of repeat expansion mutations of the same motifs in intronic sequences of TNRC6A in a family and of RAPGEF2 in the other family.

The findings that the same expanded repeat motifs in the three independent genes lead to BAFME phenotypes emphasize the role of TTTCA repeat expansions in BAFME, presumably through RNA‐mediated toxicity.

ES1‐2

A modifier of the unconventional aggregate pathologies in C9orf72‐FTLD/ALS

Kohji Mori

Department of Psychiatry, Osaka University Graduate School of Medicine

An intronic GGGGCC (G4C2) repeat expansion in C9orf72 was identified as a leading genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The hexanucleotide DNA repeat is bidirectionally transcribed into repeat RNA accumulating within RNA foci. We and others revealed the repeat RNA is even translated into five distinct proteins with dipeptide‐repeat motifs in the absence of the canonical translation initiation codon (AUG). We named these proteins as dipeptide‐repeat protein (DPR). DPR forms characteristic inclusions in C9orf72 patient's brain. Since the identification of DPR, cytotoxic properties of DPR has been extensively shown in multiple models of the disease. Repeat‐dependent toxicity in C9orf72 may affect nuclear import machinery. hnRNPA3 is a nucleo‐cytoplasmic shuttling heterogeneous nuclear ribonucleoprotein (hnRNP) that we found specifically binds to the G4C2 repeat RNA. We revealed a reduction of hnRNPA3 leads to enhanced production and deposition of DPR proteins as well as RNA foci. Moreover, reduced nuclear hnRNPA3 correlates with increased DPR depositions in the hippocampus of patients with C9orf72 repeats. In summary, we identified major constituents of the unconventional protein aggregate pathology in C9orf72‐FTLD/ALS patients. Moreover, we postulate hnRNPA3 as an endogenous modifier of the DPR and RNA aggregate pathologies. References 1. Mori K et al, EMBO Reports 17, 1314‐1325, 2016 2. Mori K et al, Acta Neuropathologica 126, 881‐893, 2013 3. Mori K et al, SCIENCE 339, 1335‐1338, 2013 4. Mori K et al, Acta Neuropathologica 125, 413‐423, 2013

Special Lecture 1 (BNS Sponsored): SL1

Understanding Alzheimer pathophysiology: implications for clinical trials

James A.R. Nicoll^1,2

¹University of Southampton; ²University Hospital Southampton

Alzheimer pathology is multi‐faceted, including accumulation of Abeta as plaques and cerebral amyloid angiopathy, tau within neurons, microglial and astrocyte activation and loss of neurons and synapses. From a neuropathological perspective, usually at a single time point and often at the end stage of the disease, it is challenging to understand the cause and effect relationships between these components. There are at least four ways of trying to unravel these relationships. Firstly, studies at early time points show pathology begins years or decades before onset of dementia, and confusingly, seem to suggest different anatomical locations for initiation of Abeta and tau accumulation. Secondly, genetic studies demonstrate mutations that influence Abeta production, but not tau, can initiate AD; whereas genetic variants influencing risk for AD are mainly related to innate immunity and lipid metabolism. Thirdly, cause and effect studies in animal models are biased by models not fully replicating AD pathology. Fourthly, clinical trials of putative therapeutic agents may alter AD giving insights into cause and effect relationships. Most trials have targeted Abeta in established AD, mainly without evidence of functional benefit; the results of preventive trials are awaited. In this context, a sequence of Abeta accumulation followed by an inflammatory reaction which promotes tau accumulation and neurodegeneration explains much of the evidence. It is proposed that different therapeutic targets are required for different stages of the disease process: Abeta for primary prevention, inflammation for secondary prevention and tau for established disease.

Symposium 8: S8‐1

Updates on the WHO Classification of Pituitary Neuroendocrine Tumors

M. Beatriz S. Lopes

Division of Neuropathology, Department of Pathology, University of Virginia

The 4th edition of the WHO Classification of Endocrine Tumors recommends changes in the classification of tumors of the pituitary gland that will be discussed in this symposium. In regard to the adenophypophysis, changes include: 1. A novel approach for classifying pituitary neuroendocrine tumors according to adenohypophyseal cell lineages; 2. Changes on the histological grading of pituitary neuroendocrine tumors with the elimination of the term atypical adenoma; 3. Introduction of new entities like the pituitary blastomas, and re‐definition of old entities like the null‐cell adenomas. The new classification is mostly based on immunohistochemistry for pituitary hormones, pituitary specific transcription factors, and markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki‐67 index, and tumor invasion is strongly recommended on individual case basis for identification of clinically aggressive adenomas. In addition, the classification provides information on prognostic significance for the treating clinical team with the identification of specific variants of adenomas with elevated risk for recurrence. Changes in the classification of non‐neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. It is hoped that the 2017 WHO classification of pituitary tumors will establish more uniform biologically and clinically groups of tumors, will facilitate the practicing pathologist to better diagnose these tumors, and contribute to understanding of clinical outcomes for patients harboring pituitary tumors.

S8‐2

Non‐functioning adenomas ‐ a new approach for their classification

Hiroshi Nishioka¹; Naoko Inoshita²

¹Dept. of Hypothalamic and Pituitary surgery, Toranomon Hospital; ²Dept. of Pathology, Toranomon Hospital

To determine adenohypophysial cell lineages for the accurate subclassification of pituitary adenomas, the new WHO classification proposed the application of transcription factors immunohistochemistry. Approximately 30‐40% of all surgically treated adenomas are clinically nonfunctioning. Morphologically they are classified into several histological subtypes with some different clinical behavior and prognosis. However, there are limitations in achieving accurate classification using hormone immunohistochemistry alone. An appropriate use of immunohistochemistry for the transcription factors has a complementary role in obtaining an accurate diagnosis for hormone‐negative adenomas. Subclassification of nonfunctioning adenomas was revised accordingly in the new classification. (1) Gonadotroph adenomas: This subtype, the most common subtype, can be reliably detected by nuclear immunoreactivity for SF‐1. Most of them are benign, slowly growing tumor presenting in middle‐aged and elderly patients. (2) Silent corticotroph adenomas: ACTH‐immunohistochemistry alone is insufficient to detect this subtype whereas assessment of Tpit expression is required for the accurate diagnosis. This subtype tends to show significant female preponderance and are more frequently large macroadenomas with marked cavernous sinus invasion. (3) Silent adenomas of pit‐1 derivation: They are morphological heterogeneous including plurihormonal pit‐1‐positive adenomas (previously called subtype 3 adenomas), et al. They typically show preponderance in younger patients and are mostly invasive, large macroadenomas with a high Ki‐67 proliferation index. (4) Null cell adenomas: The definition of this subtype was revised extensively in the new classification as follows: those composed of adenohypophysial cells that do not show any evidence of cell‐type specific differentiation using pituitary hormones and transcription factors. Consequently, they became quite rare.

S8‐3

Updates on TTF‐1 Expressing Posterior Pituitary Tumors

David Capper^1,2; M. Beatriz S. Lopes³

¹Institute of Neuropathology, Charité‐Universitätsmedizin Berlin; ²German Cancer Consortium (DKTK), Partner Site Berlin/German Cancer Research Center (DKFZ), Heidelberg, Germany; ³Department of Neuropathology, University of Virginia Medical Center, Charlottesville, VA, USA

TTF‐1 expressing posterior pituitary tumors comprise pituicytoma, granular cell tumor of the sella region and spindle cell oncocytoma. This update will focus on the histopathology and current status of molecular understanding of these rare neoplasms.

S8‐4

Updates on Craniopharyngiomas

Sandro Santagata^1,2,3,4,5

¹Department of Pathology, Brigham and Women's Hospital; ²Lab for Systems Pharmacology, Harvard Medical School; ³Ludwig Center at Harvard; ⁴Department of Oncologic Pathology, Dana Farber Cancer Institute; ⁵Department of Pathology, Boston Children's Hospital

Craniopharyngiomas are uncommon neoplasms of the central nervous system that arise above the sella turcica of the skull base. Although the tumors have benign histology, their proximity to critical neurological areas leads to extensive morbidity including pan‐hypopituitarism, visual impairment, cognitive alterations, hyperphagia and morbid obesity. Craniopharyngioma comprise two variants: adamantinomatous craniopharyngioma (ACP) which arise in children and adults and papillary craniopharyngioma (PCP) which arise nearly exclusively in adults. These two variants can be defined based on integrated histologic and genetic analysis. In addition to distinct histologic features, ACP and PCP have different patterns of gene expression and DNA methylation. Moreover, most ACP have activating mutations in CTNNB1, the gene which encodes the beta‐catenin protein, whereas nearly all PCP have BRAF V600E mutations. Several reports indicate that PCP can be highly sensitive to targeted therapy and a clinical trial is underway to evaluate the efficacy of this approach. Effective medical therapies for ACP are lacking. International research efforts continue to shed light on the importance of various signaling pathways in the development of ACP and studies are beginning to characterize the expression of immune checkpoint markers and the features of immune infiltrates in ACP and PCP. Murine models of ACP including new patient derived xenograft models are an important resource for exploring the biology of these challenging tumors and for testing therapeutic strategies.

Oral 6: O6‐1

Ultrastructural mechanisms of macrophage‐induced demyelination in chronic inflammatory demyelinating polyneuropathy: an observation on longitudinal sections

Haruki Koike; Yuki Fukami; Ryoji Nishi; Shohei Ikeda; Yuichi Kawagashira; Masahiro Iijima; Masahisa Katsuno; Gen Sobue

Nagoya University Graduate School of Medicine

Introduction: Although recent advances in the search for autoantibodies against components expressed at the nodes of Ranvier and the paranodes have significantly contributed to clarifying the pathogenesis in a subpopulation of chronic inflammatory demyelinating polyneuropathy (CIDP) patients, the mechanisms of neuropathy in cases with classical macrophage‐induced demyelination remain unclear.

Methods: We examined longitudinal sections of sural nerve biopsy specimens from 13 patients with CIDP who exhibited macrophage‐associated myelin lesions using electron microscopy. In addition to the patients with typical CIDP, three patients with atypical CIDP were also included. To assess the relationship of macrophage‐associated myelin lesions to nodal regions, a total of 1,159 nodes of Ranvier, with middle portions that were cut perpendicularly, were identified for examination.

Results: As a whole, we found 116 macrophage‐associated myelin lesions in longitudinal sections. Of these, 39 lesions were completely demyelinated, without being associated with the nodal regions or lamellar structures of the myelin. In 90 lesions, association with the nodes of Ranvier or paranodes was not observed. In the other 47 lesions, the involvement of nodal regions was obvious. The location of such macrophage‐associated lesions appeared to deviate toward a particular segment of myelinated fiber depending on the individual case. The site that macrophages select to initiate myelin breakdown is located around the nodal regions in some patients and the internode in others.

Conclusions: It seems that components that distinguish between the nodal regions and the internode play a pivotal role in the behavior of macrophages that initiate demyelination.

O6‐2

Morphometric study of myelinated fibers in sural nerve of transthyretin familial amyloid neuropathy asymptomatic carriers: back to the archives of the Corino de Andrade Unit

Armindo Fernandes¹; Teresa Coelho²; Helena Felgueiras³; Aurora Rodrigues⁴; Pedro Oliveira¹; Antonio Guimaraes^1,4; Manuel Melo Pires^1,4; Ricardo Taipa^1,4

¹Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; ²Unidade Corino de Andrade, Department of Neurosciences, Centro Hospitalar do Porto; ³Department of Neurology, Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal; ⁴Neuropathology Unit, Department of Neurosciences, Centro Hospitalar do Porto

Introduction: Familial amyloid neuropathy (FAP) with transthyretin V30M mutation (FAP‐TTR) is the most common type of FAP. The mechanisms of nerve fiber loss in FAP have not been fully understood. An early description of pathological features in asymptomatic carriers has already disclosed abnormal findings in more than 50% of this population (Leite I, et al;1987). We recovered the archived biopsies of this study, performed additional morphometric studies and correlated this with the large clinical follow‐up now available.

Methods: Sural nerve biopsies from 83 FAP patients, 35 FAP asymptomatic carriers and 23 controls, age between 19 and 78 years, were compared.

Results: Mean age at biopsy was 48.2 (14.9 SD) for patients, 33.5 (13.9 SD) for asymptomatic carriers and 48.6 (18.6 SD) for controls. The mean duration between nerve biopsy and symptoms onset was 9.2 (7.6 SD; range from 1 to 27 years). As expected, FAP patients had loss of all fiber type modalities compared to both asymptomatic carriers and controls (p < 0.001). Interestingly, the asymptomatic carriers showed loss of small myelinated fibers when compared to controls (p < 0.01). There was a positive correlation between myelinated fiber density and time to disease onset in the asymptomatic carriers that developed early‐onset form of the disease (p < 0.01).

Conclusions: This study confirms that small fiber size loss is an initial event in FAP‐TTR, already present in asymptomatic gene carriers, starting several years before symptoms onset. These findings urge better ways to define disease onset to start treatment earlier.

O6‐3

Fluoxetine improves regenerative capacity of the skeletal muscle

Mylene Fefeu^1,2; Pierre Rocheteau^1,2; David Briand²; Gregory Jouvion²; Olivier Mir³; Katherine Nautiyal⁴; Tarek Sharshar^2,7; Raphael Gaillard^1,5; Fabrice Chretien^2,5,6

¹Centre Hospitalier Sainte‐Anne, Service Hospitalo Universitaire de psychiatrie, Paris, France; ²Institut Pasteur, Experimental Neuropathology Unit, Infection and Epidemiology Department, Paris, France; ³Department of Cancer Medicine, Gustave Roussy, University of Paris Sud, Villejuif, France; ⁴Division of Integrative Neuroscience, New York State Psychiatric Institute, and Department of Psychiatry, Columbia University, NY, USA; ⁵Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; ⁶Centre Hospitalier Sainte‐Anne, Service Hospitalo Universitaire de neuropathologie, Paris, France; ⁷Service de reanimation medico‐chirurgicale adulte, Hopital Raymond Poincare, Garches, France

Introduction: Antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase of serotonin level, neurogenesis and angiogenesis in the brain. In line with these effects, we tested whether the antidepressant could have broader regenerative properties.

Methods: To assess the effect of antidepressant on mice skeletal muscles, we administered fluoxetine at 18mg/kg daily for 6 weeks, followed by histological and cytometry analysis. To investigate whether fluoxetine may influence the regenerative capacity of skeletal muscles, we delivered fluoxetine for 6 weeks and performed a notexin‐mediated muscle injury of in Tg:Pax7‐nGFP mice in which the GFP reporter gene marks all muscle stem cells. To determine the mode of action of fluoxetine we performed the RT‐qPCR for serotonin receptor subtypes on Tg:Pax7nGFP satellite cells isolated by FACS and then confirmed their involvement in fluoxetine effects on muscle regeneration by using specific antagonists of serotonin receptors. Finally, we tested whether fluoxetine had a potential therapeutic effect on Duchenne muscular dystrophy (DMD) by treating old mdx mice with fluoxetine for 6 weeks and performed histological and functional analysis.

Results: Fluoxetine increased the number of muscle stem cells and improved skeletal muscle regeneration following injury. Beneficial effects of fluoxetine acted via the 5HT1b receptor directly on the muscle stem cells. Fluoxetine also decreased the number of lesions and increased the strength in a DMD model.

Conclusion: These results suggest a potential clinical application for fluoxetine in dystrophic diseases and in organs displaying regenerative capacities, such as the skeletal muscle.

Symposium 9: S9‐1

Progressive Multifocal Leukoencephalopathy: Virology and Neuropathology

Yukiko Shishido‐Hara

Department of Anatomic Pathology, Tokyo Medical University Hospital/Laboratory of Structural Neropathology, Tokyo Metropolitan Institute of Medical Science

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease, caused by JC virus infection in immunosuppressed individuals. Pathologically, viral inclusions are detected in the enlarged nuclei of infected oligodendroglia‐like cells, which is a diagnostic hallmark of this disease. Viral inclusions were initially noted with hematoxylin‐and‐eosin staining as amphophilic materials comprising the entire nucleus (full inclusions). Recent immunohistochemical analyses, however, revealed the presence of intranuclear viral inclusions in dots (dot‐shaped inclusions), which reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies (PML‐NBs). Normal oligodendroglia has compact small nuclei, but after virus infection, nuclear enlargement occurs with cell‐cycle activation from S to G2. In the enlarging nuclei, PML‐NBs also grow larger, where JC virus reproduces progenies to form dot‐shaped inclusions. The progenies later fulfil the entire part of the nucleus and disrupt PML‐NBs. Since PML‐NBs are important for nuclear events, such as transcription, DNA replication, and cell‐cycle regulation, PML‐NBs dysruption may induce death of host cells. Today, PML development in MS patients under disease modifying therapy (DMT) is a worldwide concern. Since early diagnosis of PML is essential for favourable outcome, understanding early pathological features of affected cells may help diagnosis in case of brain biopsy.

S9‐2

CADASIL and CARASIL: pathologic features and possible pathomechanisms

Rie Saito, Akiyoshi Kakita

Department of Pathology, Brain Research Institute, Niigata University

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are hereditary cerebral small‐vessel diseases (CSVD) leading to stroke and vascular dementia in adults. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the Notch3 receptor expressed in vascular smooth muscle cells (SMCs). The Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by SMC degeneration and subsequent fibrosis. Diagnosis is based on characteristic microscopic features such as granular osmiophilic material and N3ECD immunopositivity of SMCs, as well as genetic profiling. The pathogenesis of CADASIL is thought to be toxic gain of function related to a mutation‐induced unpaired cysteine in N3ECD. Moreover, recent studies have provided new insight into the pathogenetic role of excess extracellular matrix proteins, including vitronectin and timp3. Despite having a similar clinical picture and white matter changes, CARASIL is much rarer than CADASIL. In addition, spondylosis deformans and early‐onset alopecia are frequent features. High‐temperature requirement serine peptidase A1 (HTRA1) gene mutations and a consequent decrease of HTRA1 protease activity cause CARASIL. Even though CARASIL is a recessive inherited disease, recent studies have identified patients with symptomatic CSVD with heterozygous mutations in HTRA1. We have observed that patients with heterozygous mutations and “CARASIL” share similar pathological findings including loss of SMCs and splitting of the internal elastic lamina with marked hyalinosis of cerebral arteries. We summarize the clinicopathologic features of CADASIL and CARASIL, and discuss their possible pathomechanisms.

S9‐3

Neuronal intranuclear inclusion disease (NIID)

Jun Sone

Department of Neurology, NHO Suzuka National Hospital

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the central and peripheral nervous system, and in the visceral organs. We studied clinical and pathological features of NIID case, and made out the diagnostic flowchart of NIID. We studied 97 sporadic NIID cases and 23 familial NIID cases. 2 sporadic cases and 3 familial cases were also studied autopsy, and most of cases were performed skin biopsy. All histological samples were stained by hematoxylin & eosin, and immunostained with anti‐ubiquitin and anti‐p62 antibody. In the sporadic NIID cases, dementia was the most prominent initial symptom, followed by miosis, ataxia and unconsciousness. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently, followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent. Elevated CSF protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head MRI showed high intensity signal in corticomedullary junction in diffusion weighted image (DWI) in both sporadic and familial NIID cases. All of the dementia dominant cases presented with this type of leukoencephalopathy on head MRI, and with a decline in MMSE and FAB scores. The number of antemortem diagnosed NIID cases is increasing dramatically. We must consider NIID as a differential diagnosis of leukoencephalopathy and neuropathy, utilizing the NIID diagnostic flowchart.

S9‐4

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): pathologic features suggestive of “microgliopathy”

Mari Tada, Akiyoshi Kakita

Department of Pathology, Brain Research Institute, Niigata University

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal‐dominant progressive dementia, characterized pathologically by widespread loss of myelin sheaths and axons with axonal spheroids and macrophage infiltration. The causative gene of ALSP encodes the colony stimulating factor 1 receptor (CSF1R). CSF1R is a cell‐surface receptor that regulates the survival, proliferation, differentiation and function of mononuclear phagocytes. In the CNS, the receptor is expressed predominantly in microglia, and therefore ALSP has recently been considered one of the primary microglial disorders known as microgliopathies. However, there has been little direct evidence to characterize ALSP as a microglial disorder. We have recently reported several unique histological features of microglia in the brains of ALSP patients. Activated microglia are spatially restricted rather than being distributed diffusely, despite the presence of diffuse white matter degeneration. The microglia show relatively uniform and delicate morphology with thin processes and many knot‐like structures. The microglia in less affected regions are reduced in number relative to control brains, although Ki67‐expressing proliferative microglia are frequently observed in areas of dense microglial distribution. Ultrastructurally, the microglial cytoplasm and processes show vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating impairment of protein synthesis. These findings suggest that the pathogenesis of ALSP is associated with microglial vulnerability and morphological alterations. Further investigations to clarify the underlying roles of microglia in this type of leukoencephalopathy are needed in order to develop suitable therapy.

Oral 7: O7‐1

The genetic landscape of pediatric low‐grade gliomas: incidence, prognosis and response to therapy ‐ a SickKids pLGG Task Force Update

Cynthia Hawkins^1,2; Scott Ryall²; Michal Zapotocky³; Kohei Fukuoka³; Ana Guerreiro‐Stucklin³; Eric Bouffet³; David Ellison⁴; Uri Tabori³

¹Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; ²Laboratory Medicine and Pathobiology, The University of Toronto; ³Division of Haematology‐Oncology, the Hospital for Sick Children; ⁴Pathology Department, St Jude Children's Research Hospital

Molecular characterization of pediatric low‐grade glioma (pLGG) over the last decade has identified recurrent alterations, most commonly involving BRAF. Many of these molecular markers have been exploited clinically to aid in diagnosis and treatment decisions. However, their frequency and prognostic significance remain unknown. Further, a significant proportion of cases do not have any of these alterations and what underlies these cases is also unknown. To address these questions we compiled a cohort of 593 patients diagnosed with pLGG at SickKids from 2000‐2017 of which 117 were non‐biopsied NF‐1 and 521 had sufficient tissue for molecular analysis. We identified molecular alterations in 419 cases (81% of the cohort). The most frequent events were those involving BRAF; either as fusions (most commonly with KIAA1549 (31%)) or V600E mutations (14%), and NF‐1 (22%). Less frequently, we identified FGFR1 fusions and mutations (3%), MYB/MYBL alterations (2%), H3F3AK27M (2%) or IDH1R132H (0.5%) mutations, as well as other novel rare events. Survival analysis revealed significantly better progression‐free survival (PFS) and overall survival (OS) of KIAA1549‐BRAF fused patients compared to BRAFV600E with 10‐year OS 97.7% (95%, CI 95.5‐100) and 83.9% (95%, CI 72.5‐95.6), respectively. In patients with MYB/MYBL1 or FGFR1/FGFR2 alterations, we observed only one death (FGFR1N546K case). While patients with H3F3AK27M had median PFS of only11 months. Beyond survival, molecular alterations predicted response to conventional therapeutics; BRAF fused patients showed a 46% response‐rate, versus only 14% in V600E patients. This represents the largest cohort of molecularly profiled pLGGs and their impact on clinical behaviour.

O7‐2

Improved diagnostic algorithm for differential diagnostics of CNS embryonal tumors (former CNS‐PNET) by neuropathological re‐evaluation of 256 cases and crossvalidation by methylation classification

Torsten Pietsch^1,2; Dominique Figarella‐Branger³; Felice Giangaspero⁴; Cynthia Hawkins⁵; Thomas S. Jacques⁶; Charles Eberhart⁷; Peter Burger⁷; Marcel Kool⁸; Katja von Hoff⁹; Christine Haberler¹⁰

¹Institute of Neuropathology, University of Bonn, Germany; ²DGNN Brain Tumor Reference Center; ³Department of Pathology and Neuropathology, Aix Marseille University, France; ⁴Department of Pathology, Sapienza University Rome, Italy; ⁵The Hospital for Sick Children, Toronto, Canada; ⁶UCL Great Ormond Street Institute of Child Health, London, U.K.; ⁷Department of Pathology, Johns Hopkins University, Baltimore, USA; ⁸DKFZ, Heidelberg, Germany; ⁹Department of Pediatric Hematology/Oncology, Hamburg University Medical Center, Hamburg, Germany; ¹⁰Department of Neuropathology, University of Vienna, Austria

Introduction: Epigenetic profiling has shown that a proportion of cases diagnosed as CNS‐PNET in the past can be assigned to other tumour entities with similar morphological appearance.

Methods: In an international effort to re‐analyze CNS‐PNET aiming for disease‐specific re‐evaluation of survival data and the development of diagnostic guidelines providing the basis for improved therapeutic approaches, 256 tumours diagnosed and treated as CNS‐PNET in the last two decades in 17 countries were reviewed by a panel of neuropathologists according to today's standards of clinical neuropathological diagnostics including immunohistochemical and molecular pathological assays. The majority of cases were also independently analyzed by methylation array hybridization and classified by random forest algorithm.

Results: In this unique cohort, we identified 20 different tumor entities including frequent high grade gliomas. 41% of cases were confirmed as CNS‐PNET (now termed CNS‐embryonal tumors (CNS‐ET) according to the revised WHO‐classification) representing two main entities: ETMR displayed typical histological features, LIN28A expression and/or C19MC alteration. The other represented a group of tumors with variable degrees of neuroblastic/ganglionic differentiation, corresponding to the WHO diagnoses CNS‐(Ganglio)‐neuroblastoma or CNS‐ET, NOS. The vast majority of these tumors could be assigned to the FOXR2 CNS‐NB group by methylation array‐based classification.

Conclusions: Crossvalidation of neuropathological and epigenetic classification proved that methylation classification represents a useful complimentary tool in the differential diagnosis of CNS‐ET. Re‐evaluation of prototypic tumors and discrepant cases enabled us to develop an optimized diagnostic algorithm to securely delineate this tumor from other entities with largely divergent clinical and biological behaviour.

O7‐3

Value of Immunohistochemistry and Sequencing for Detection of the H3.3 G34 Mutations in High Grade Gliomas

Francesca Gianno^1,6; Manila Antonelli¹; Tiziano Di Dio¹; Francesca Diomedi²; Anna Maria Buccoliero³; Mariangela Novello⁴; Vittoria Donofrio⁵; Francesco Fiorentino¹; Antonella Arcella⁶; Felice Giangaspero^1,6

¹Department of Radiological, Oncological and Anatomo‐pathological Sciences, University Sapienza, Rome, Italy; ²Department of Laboratories, Pathology Unit, Bambino Gesu Children's Hospital, IRCCS; ³A. Meyer Children's University Hospital, Pathology Unit Florence, Italy; ⁴Anatomic Pathology Unit, Vicenza Hospital, Vicenza, Italy; ⁵Anatomic Pathology Unit, Santobono‐Pausilipon Children's Hospital, Naples, Italy; ⁶IRCCS Neuromed, Pozzilli, Italy

Introduction: Recurrent glycine‐to‐arginine/valine alterations at codon 34 (G34R/V) within H3F3A gene occur in hemispheric high grade gliomas (HGG) of children/young adults. These tumors are histologically heterogeneous, with microscopic features of either glioblastoma/anaplastic astrocytoma (GBM/AA) or embryonal tumors (PNET‐like). To assess the value of immunohistochemistry (IHC) to detected H3.3G34 mutated cases, we tested an anti‐histone H3.3G34V (Clone329E5) and anti‐histone H3.3G34R (CloneRM240) antibodies in a series of 25 formalin fixed and paraffin‐embedded (FFPE) samples.

Methods: Twenty‐five cases of HGG were evaluated by immunohistochemistry and 17/25 by sequencing. The median age was 19 years (4‐78 years). All cases were hemispheric. Histologically 20/25 were GBM/AA and 5/25 cases were PNET‐like.

Results: By immunohistochemistry, 8/25 cases showed nuclear positivity for H3.3G34R and 1/25 for H3.3G34V. By targeted sequencing, performed in 17/25 cases, 7/17 cases showed mutations: 6 H3.3G34R and 1 H3.3G34V. All 7 cases mutated by sequencing resulted positive by IHC. However, two out nine cases positive by IHC resulted wild type by sequencing. Moreover, 6/7 of mutated cases showed loss of ATRX expression and/or p53 expression, and 1/7 was ATRX‐positive and p53‐negative. All cases were negative for IDH mutations.

Conclusion: 1) Positivity by IHC is highly predictive for H3.3 G34 mutation but confirmation by sequencing is mandatory; 2) Negativity by IHC indicates absence of mutations; 3) H3.3 G34 mutations should be suspected in all hemispheric tumor IDH1/2 wild type, showing loss of ATRX and/or p53 expression.

O7‐4

Grading of pediatric high grade gliomas. Results from the HERBY trial

Pascale Varlet¹; Gwenael Le Teuff²; Marie‐Cecile Le Deley³; Felice Giangaspero⁴; Christine Haberler⁵; Thomas Jacques⁶; Dominique Figarella‐Branger⁷; Torsten Pietsch⁸; Felipe Andreiuolo¹; Jacques Grill²

¹Department of Neuropathology, Sainte‐Anne Hospital, Paris, France; ²Institut Gustave Roussy, Villejuif, France; ³Centre Oscar Lambret, Lille, France; ⁴Sapienza University of Rome, Roma and IRCCS Neuromed, Pozzilli (Is); ⁵Institute of Neurology, Wien, Austria; ⁶UCL GOS Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom; ⁷Hopital de la Timone, Marseille, France; ⁸University Bonn, Bonn, Germany

The glioma grading system initially designed for diffuse adult gliomas is questionable in pediatric high grade gliomas (HGG), which are biologically distinct from their adult counterparts. This issue was addressed from HERBY randomized phase‐II trial (NCT01390948) with newly‐diagnosed non‐brainstem HGG Methods: A real‐time central pathology review (WHO‐2007) was mandatory before randomization, followed by a consensus review including five other independent experts. We evaluated the inter‐observer agreement for grading (Kappa coefficients); the discriminant ability of elementary grading criteria associated with III / IV grade (logistic regression); the prognostic value of grade, midline location and selected biomarkers (Mib‐index, CD34, EGFR, p53, H3K27Mut) on event‐free survival (EFS) and overall survival (OS) (Cox models). Findings: Among the 124 evaluable cases, inter‐observer agreement was substantial for HGG‐grading (Kappa = 0.81), vascular proliferation (Kappa = 0.74) and necrosis (Kappa = 0.85), but moderate for the four other criteria (differentiation, cellular density, atypia, mitosis: Kappa < 0.60). Adding these four criteria did not significantly increase the discriminant ability as compared to the combination of vascular proliferation and necrosis (AUC=0.99 vs 0.97, p=0.24). High Mib‐index was more frequent in grade‐IV than in III. Among the 118 confirmed and randomized HGG, neither the different grading criteria, nor the resulting grade were found significantly associated with survival outcomes (in midline and non midline HGG). Midline location and a high Mib‐index were both associated with poor EFS (HR=2.33 [95%CI=1.38‐3.92] and 2.57 [1.39‐4.74) and OS (HR=2.57 [1.36‐4.88] and 2.06 [1.04‐4.10]) in multivariable analysis. Conclusion: These data highlight that WHO‐grading for HGG is questionable in children with respect to prognostication

O7‐5

Immunohistochemical and molecular subtyping of Central Nervous System Primitive neuroectodermal tumors (CNS PNETs) in light of the updated 2016 WHO classification

Mehar Chand Sharma¹; Niteeka Gurung¹; Amandeep Kumar²; Vaishali Suri¹; Manmohan Singh²; Chitra Sarkar¹

¹Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi; ²Department of Neurosurgery, AIIMS, New Delhi

Introduction: Poorly differentiated embryonal tumors previously designated as Central Nervous System Primitive neuroectodermal tumors (CNS PNETs) encompass heterogeneous entities with specific molecular alterations. Embryonal tumor with multilayered rosettes is one such subtype, characterized by C19MC amplification and lin28A immunoexpression (ETMR, C19MC altered). Those lacking specific molecular alterations are now termed CNS embryonal tumor, NOS. We aimed to reclassify CNS PNETs according to current WHO 2016 classification, and evaluate true incidence of CNS embryonal tumors, NOS, in a tertiary healthcare setting.

Methods: CNS PNETs (negative for t(11:22), immunonegative for MIC2, RelaA, L1CAM, IDH1R132H, and H3K27M proteins, retained INI1) underwent immunohistochemistry for Lin28A and Olig2, and FISH for C19MC amplification. Ten cases each of medulloblastoma, ATRT, pineoblastoma, Ewing sarcoma and esthesioneuroblastoma were included as controls.

Results: Among 22 cases of CNS PNETs included, 2 showed C19MC alteration (ETMR, C19MC altered). Both showed medulloepithelioma morphology and Lin28A immunopositivity. No other tumor, including controls, showed C19MC alteration, while 27% ATRTs showed false positive staining for Lin28A. 14% of CNS PNETs showed Olig2 positivity of which all showed classical morphology and were negative for C19MC amplification and Lin28A. None of the controls was Olig2 positive.

Conclusion: Among CNS embryonal tumors, ETMR C19MC altered constitute less than 10% with majority remaining uncharacterized as CNS embryonal tumors, NOS. Lin28A is a sensitive immunohistochemical marker for identification of ETMR. However, its specificity is limited by its expression in ATRTs.

Special Lecture 2: SL2

Neuropathologic heterogeneity in autosomal dominant and late‐onset Alzheimer disease

Nigel J. Cairns¹; the Dominantly Inherited Alzheimer Network²; the Alzheimer Disease Neuroimaging Initiative³

¹Department of Neurology, Washington University, Saint Louis, Missouri, USA; ²Dominantly Inherited Alzheimer Network (DIAN), http://dian‐info.org; ³Alzheimer Disease Neuroimaging Initiative (ADNI), http://www.adni‐info.org/

Introduction: In the design of clinical trials, it has been proposed that autosomal dominant AD (ADAD) may be a useful model of the more frequent late‐onset AD (LOAD). ADAD has a predictable age at onset, clinical course, and biomarker and neuroimaging trajectories, yet the neuropathology of these clinically well‐characterized cohorts has not been systematically studied.

Methods: The Neuropathology Laboratory of the Knight Alzheimer Disease Research Center served as the single central laboratory for both DIAN and ADNI which enabled standardized neuropathologic assessments of all ADNI participants (n=63) who came to autopsy and participants (n=19) and family members (n=18) at DIAN sites. Histology included hematoxylin and eosin and immunohistochemistry was performed to detect four frequent molecular pathologies: Amyloid‐beta (10D5; Eli Lilly), phospho‐tau (PHF1; gift of P. Davies), phospho‐alpha‐synuclein (Cell Applications, Inc.), and phospho‐TDP‐43 (Cosmo Bio USA).

Results: Of 63 ADNI participants with AD dementia at expiration, 96% cases had AD neuropathologic change (ADNC); two cases had argyrophilic grain disease (AGD) and primary age‐related tauopathy (PART). All 37 DIAN cases had florid ADNC at expiration. Twenty‐two of 37 (59%) DIAN cases had diffuse Lewy body disease or amygdala‐predominant Lewy body disease. In the ADNI cohort, 49% had Lewy body disease. Other comorbidities in LOAD included TDP‐43 proteinopathy (30%), argyrophilic grain disease (19%), hippocampal sclerosis (8%), infarcts (5%), and aging‐related tau astrogliopathy (14%). These comorbidities were absent in ADAD.

Conclusion: Both ADAD and LOAD have significant synucleinopathy (Lewy bodies) comorbidity in up to one half of cases. LOAD cases are distinguished from ADAD by the presence of age‐related pathology. The presence of additional age‐related pathologies in LOAD may indicate that a more complex therapeutic approach is required in this group in comparison with ADAD.

Symposium 10: S10‐1

Neuropathological experience with 2244 LEAT from the European Epilepsy Brain Bank

Ingmar Blümcke

Institute of Neuropathology, University Hospitals Erlangen

We have histopathologically described a series of 9523 patients with focal epilepsy submitted to epilepsy surgery in 36 centers across 12 European countries (the European Epilepsy Brain Bank consortium; Blumcke et al. 2017; NEJM, 377:1648‐56). Low‐grade epilepsy‐associated brain tumours (LEAT) are the second most common structural lesions identified, i.e. ganglioglioma and dysembryoplastic neuroepithelial tumours, and comprise 69percent of brain tumours in our series. LEAT share the following catalogue of histopathological and clinical features: (1) >70percent of tumors occur in temporal lobe; (2) they provoke seizure onset at mean age of 15y, were operated after disease duration of 16y, and > 70percent of patients were seizure free 1y after surgery; (3) > 90percent of LEAT behave clinically in a benign manner and correspond to WHO I. There is no definition of atypia (WHO II) for these tumours in the current WHO classification; (4) LEAT have a histologically variable appearance with oligodendroglial or astrocytic phenotypes with or without a prominent dysplastic neuronal component; (5) LEAT may be associated with cortical dysplasia (FCDIIIb); (6) LEAT lack IDH1/2 mutations or 1p/19q co‐deletions. Instead, molecular alterations in RAS–RAF–MAPK and PI3K–AKT–mTOR signaling pathways prevail. Throughout all editions of the WHO classification, however, histopathological definitions of and descriptions for the broad spectrum of LEAT variants remain incomplete, thereby challenging the daily routine microscopic work‐up. This symposium will tackle difficulties in classifying LEAT from various angles and discuss how to accomplish a reliable genotype‐phenotype classification conform with WHO standards in the near future.

S10‐2

The differential diagnosis of ganglioglioma and DNT variants: avenues towards an integrated phenotype‐genotype classification

Maria Thom

Department of Neuropathology, Institute of Neurology, University College London (UCL)

In the setting of long‐term epilepsy, specific types of low‐grade tumours can be grouped under the umbrella term ‘LEAT’ (low‐grade epilepsy‐associated tumours). LEATS are commonly located in the temporal lobe, typically present in late childhood, with epilepsy as the primary and often only neurological symptom. Many LEATs represent glioneuronal tumours with a mixed cell composition and are typically low grade (WHO grade I). Based on the WHO revised classification of brain tumours (2016) the two main tumour types encountered are ganglioglioma (GG) and dysembryoplastic neuroepithelial tumours (DNT). However many LEATs are difficult to classify using current WHO criteria: For example (i) many show diffuse growth patterns and lack the characteristic histology features of DNT or ganglioglioma, (ii) others can show mixed/composite features, (iii) in addition new LEAT tumour types continue to be described for example multinodular and vacuolated neuronal tumours and polymorphous low‐grade neuroepithelial tumor of the young (PLNTY) that can histologically mimic DNT and GG. Agreement studies between pathologists, based on refined histological criteria alone, have shown to be insufficient. Advances in the molecular biology of LEATs with an integrated phenotype‐genotype classification will be inevitable to improve their recognition and ultimately refine the classification of the LEAT and DNT‐GG spectrum. There is evidence of involvement of the PI3K‐AKT‐mTOR and RAS‐RAF‐MAPK in the LEAT group and identification and study of common mutations to LEAT subtypes, as well providing diagnostic security, could indicate avenues for non‐surgical treatments.

S10‐3

Pleomorphic Xanthoastrocytoma: Pathology and Genetics

Caterina Giannini

Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic

Pleomorphic xanthoastrocytoma (PXA) frequently represented in epilepsy surgery series shares with long‐term epilepsy associated neuroepithelial tumors (LEATs) the young onset age, the superficial cortical location, temporal lobe predilection and often slow growth rate. PXA has a less favorable prognosis than other LEATs with higher frequency of recurrence following surgical removal and a tendency to progression, prompting a WHO grade II designation. Histopathologically PXA is characterized by cellular pleomorphism with spinded and giant often multinucleated cells, xanthomatous change with cytoplasmic lipid droplets and frequent eosinophilic granular bodies, brightly eosinophilic and pale. Pericellular reticulin deposition is frequent. High mitotic activity (five or more mitoses per 10HPF) now defines anaplastic PXA (WHO grade III). Necrosis is frequent in anaplastic tumors, but its significance independently of mitotic activity remains indeterminate. Similar to other LEATs, PXA frequently shows BRAF V600E mutation (near 60%), which is more common in low‐grade (WHO grade II) than high (WHO grade III) and associated with favorable outcomes, although it is unclear whether BRAF V600E is prognostically independent of tumor grade. CDKN2A/B homozygous deletion is present with equal frequency (near 90%) in classic (WHO grade II) and anaplastic (WHO grade III) tumors. Additional copy number alterations, including whole chromosomes or whole arm gains, losses and copy‐neutral loss of heterozygosity, are frequent. These indings were confirmed in a recent study in which the authors found TERT to be the third most commonly altered gene in anaplastic PXA (alterations including gene amplification and mutations), and suggested its association with anaplastic transformation.

S10‐4

Brain somatic mutations in MTOR and BRAF leading to intractable focal epilepsy

Jeong‐Ho Lee

Korea Advanced Institute of Science and Technology (KAIST)

Mutations occur during cell division in all somatic lineages due to the unavoidable DNA replication errors. Because neural stem cells continue to undergo cell division throughout human life, somatic mutations in human brain can arise during development and accumulate with the aging process. Although somatic diversity is an evident feature of the brain, the extent of somatic mutations affecting the neuronal structure and function and their contribution to neurological disorders remain largely unexplored. Recently, we have provided the molecular genetic evidence that brain somatic mutations indeed lead to intractable focal epilepsy. In this symposium, I will present our recent findings regarding brain somatic mutations as potential molecular lesions underlying intractable focal epilepsy, thereby providing a new insight into the molecular pathogenesis and therapeutics for the related disorders.

Symposium 10: S10‐5

New prospects for the classification of pediatric low‐grade gliomas and glioneuronal tumors

David W. Ellison

St. Jude Children's Research Hospital

Neural tumors presenting in childhood often differ from their counterparts in adult patients. This is true of low‐grade diffuse gliomas, IDH‐wildtype / H3‐wildtype tumors that have a distinct genetic profile and biologic behavior when presenting in children or adults. Attempts to delineate such tumors by molecular criteria need to account for the complex overlap between histologic and genetic features across the range of low‐grade gliomas and glioneuronal tumors that present in children and young adults.

Oral 8: O8‐1

High‐grade gliomas involving the subventricular zone ‐ a molecular study of 32 cases

Aden Ka‐yin Chan, Riki Rui‐qi Zhang, Ho Keung Ng

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong

Introduction: High‐grade gliomas abutting on the subventricular region have been described to show aggressive features and poor outcomes but there has been no detailed study of molecular features of these tumors.

Methods: We studied 32 such tumors from our archives, all except one being glioblastomas, for their clinical features and examined amplifications of c‐myc, MYCN, EGFR, mutations of H3F3A‐K27M, TERTp, IDH1‐R132H, 10q deletion and by immunohistochemistry ATRX, nestin and SOX2.

Results: c‐Myc and MYCN were each amplified in 32.3% and together were amplified in 58% of the cases. This is in contrast to information derived from TCGA dataset where c‐Myc and MYCN were only rarely amplified in glioblastoma. MYCN in addition was associated with younger age (p=0.029), concomitant H3F3A‐K27M mutation (p=0.002), non‐amplified EGFR (p=0.023) and mid‐line location (p=0.012). Interestingly, we found a low percentage of TERTp mutation (19%) among these high‐grade gliomas which was mutually exclusive with a higher frequency of ATRX loss (p=0.025). The majority (91%) of tumors were IDH wildtype and 39% of them were deleted for 10q. Moreover, 97% of cases expressed at least one of the stem cell markers, which may be related to the supposedly subventricular location of neural stem cells. 89% of cases relapsed with 50% showing CSF dissemination. However, there was no statistical relationship between survivals and biomarkers or other clinical parameters.

Conclusion: In conclusion, our study has identified a subgroup of subventricular zone high‐grade gliomas characterized by c‐Myc, MYCN amplification and frequent expression of stem cell markers and a high rate of CSF dissemination.

O8‐2

INI‐1 immunohistochemistry in CNS embryonal tumors ‐ a clinicopathological study

Lily Pal¹; Ananth Mehrotra²; Shalini Singh³

¹Department of Pathology, SGPGIMS; ²Department of Neurosurgery, SGPGIMS; ³Department of Radiotherapy

Introduction: Central nervous system embryonal neuroepithelial tumors are highly malignant, heterogenous group of neoplasms and medulloblastoma is the most common entity in children. Nuclear expression of hSNF5/INI‐1, a tumor suppressor gene is retained in medulloblastomas, pineoblastomas and other embryonal tumors enabling distinction from atypical teratoid/rhabdoid tumor (AT/RT) with dismal prognosis. Embryonal tumors without rhabdoid morphology are often difficult to diagnose and hence this study was undertaken.

Material & methods: 141 cases of CNS embryonal tumors were retrieved from the archives of Pathology SGPGIMS, comprising of medulloblastoma (103), pineoblastoma (4), AT/RT(15), Embryonal tumor with multilayered rosettes (ETMR 2), CNS neuroblastoma (1) and CNS embryonal tumor NOS(16). Immunohistochemistry for INI‐1 protein was performed in all these cases along with GFAP, synaptophysin, desmin, Vimentin, EMA, SMA and cytokeratin as and when required.

Results: Majority of medulloblastomas ( 94/103) expressed INI‐1 and there was no significant difference across histological subtypes. One half of AT/RTs were in the age group of 9 months to 3 years and all showed loss of INI‐1 protein. Immunohistochemically all AT/RTs had polyphenotypic nature and were negative for desmin. INI‐1 was retained in rest of the embryonal tumors.

Conclusion: Medulloblastomas and other embryonal tumors including AT/RTs often have clinical, radiological and histological overlapping features. Prognosis for patients with AT/RT is worse than other embryonal tumors due to poor response to conventional therapy. Therefore INI‐1 immunohistochemistry routinely in all malignant pediatric embryonal may help to identify INI‐1 negative tumors and may be benefit from accelerated treatment.

O8‐3

Histopathologic description and identification of prognostic factors for infantile desmoplastic gangliogliomas and astrocytomas

Perbet Romain^1,2; Maurage Claude‐Alain^1,2; Varlet Pascale³; Jouvet Anne⁵; Silva Karen⁵; Gourmel Antoine⁴

¹School of Medecine, University of Lille, France; ²Pathology Institute, Lille University hospital, France; ³Department of Pathology, Sainte‐Anne Hospital, France; ⁴Department of Pediatric Oncology, Amiens University Medical Center, Amiens, France; ⁵Service de Neuropathologie, Groupe Hospitalier Est, Hospices Civils de Lyon, Lyon, France

Introduction: Desmoplastic infantile gangliogliomas (DIG) and desmoplastic infantile astrocytomas (DIA) are rare cerebral tumors; their prognostic factors are not well established, especially regarding histopathological and molecular criteria.

Methods: All DIG/DIA diagnosed in France from January 1998 to December 2016 were included in this retrospective study. The main objective was to assess the prognostic impact of histopathological and molecular criteria on progression‐free survival (PFS). The following criteria were analyzed: necrosis (present vs. absent), microvascular proliferation (present vs. absent), mitotic count, cellular area (surface rate), poorly differentiated neuroepithelial component (surface rate), desmoplasia (surface rate), Ki‐67 and olig2 labeling index, neuronal markers expression (present vs. absent), chromosomal alteration (CGH array) and BRAF mutation status.

Results: 37 patients were included in this study. The 5‐year overall survival and PFS were 93% and 72% respectively (median follow up of 57 months). Four patients died of disease and 13 patients relapsed. Total surgical resection was not associated with a higher PFS (p = 0.88). High mitotic count (HR = 1.189; p < 0.001), high Ki‐67 labeling index (HR = 1.056; p = 0.005), high cellular area (HR = 1.017; p = 0.019), poorly differentiated neuroepithelial component (HR = 1.042; p = 0.039), any chromosomal alteration (HR = 4.890; p = 0.021) and BRAF mutation (HR = 4.350; p = 0.020) were associated with a lower PFS.

Conclusions: These tumors display several microscopic features that can mimic high grade brain tumors. Standard stain examination, Ki‐67 index, CGHarray and BRAF mutation status are of interest as predictors of outcome.

O8‐4

Presence of H3 K27M mutation in a series of midline children/young adults gliomas

Jose Pimentel^1,2; Lucia Roque³; Claudia Faria⁴; Rafael Roque¹

¹Laboratorio de Neuropatologia, Servico de Neurologia, Departamento de Neurociencias, Hospital de Santa Maria; ²Faculdade de Medicina, Universidade de Lisboa; ³ Unidade de Investigacao em Patobiologia Molecular, Instituto Portugues de Oncologia de Lisboa Francisco Gentil; ⁴Servico de Neurocirurgia, Departamento de Neurociencias, Hospital de Santa Maria; ⁵Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa

Introduction: Conventionally, gliomas with the Histone H3‐K27M mutation arise in children/young adults in the midline, and are linked to a poor prognostic unrespect the anaplasia degree.

Material and Methods: All gliomas arising in the midline in children/young adults with the presence of the mutation demanded during the diagnostic work‐up. The following antibodies (abs) were performed: GFAP, Olig2, ATRX, IDH1, S100, MAP2, and P53. K27M mutation analysis was obtained by sequencing after the histological diagnosis.

Results: Seven patients, 4 males, aged between 2 and 32 years, with gliomas in the spinal cord (1), pons (4), thalamus (1) and 3th ventricle (1). Histomorphological diagnostics were pylocitic astrocytoma (2), anaplastic astrocytoma (1), and glioblastoma (4). Surgeries were ressective (2) and stereotaxic biopsy (5). All patients did the standard postsurgery treatment. All patients died between 1 and 11 months after surgery. All cases were GFAP positive, IDH1 negative, and ATRX non mutated. For the rest of the abs, positivity for S100, Olig2 and MAP2 for all cases, and for P53 in 3.

Discussion/Conclusion: The approach of this series was mainly the standard one and data was similar to previously ones regarding clinical, histopathology and immunohistochemistry features. Enlarged field of clinical and histomorphological gliomas`recruitment will probably increase the presence of H3‐K27M mutation and change the paradigm of these tumors.

O8‐5

An integrative radiological, histopathological and molecular analysis of pediatric pontine MYCN‐HGG

Arnault Tauziede‐Espariat¹; Marie‐Anne Debily²; David Castel²; Stephanie Puget³; Magnus Sabel⁴; Klas Blomgren⁵; Jacques Grill^2,6; Volodia Dangouloff‐Ros⁷; Nathalie Boddaert⁷; Pascale Varlet¹

¹Department ofDepartment of Neuropathology, Sainte‐Anne Hospital, 75014 Paris, France; ²UMR8203 Vectorologie et Therapeutiques Anticancereuses CNRS, Gustave Roussy, Univ. Paris‐Sud, Universite Paris‐Saclay, Villejuif, France; ³Department of Paediatric Neurosurgery, Necker Hospital, APHP, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; ⁴Department of Paediatric Oncology, Childhood Cancer Centre Queen Silvia Children's Hospital Sahlgrenska University hospital, Goteborg, Sweden; ⁵Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden; ⁶Departement de Cancerologie de l Enfant et de l Adolescent, Gustave Roussy, Univ. Paris‐Sud, Universite Paris‐Saclay, 94805, Villejuif, France; ⁷Department of Radiology, Necker Hospital, APHP, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France

Introduction: Diffuse midline glioma, H3K27M‐mutant was recently introduced in the 2016 WHO classification of CNS tumors and represents the main tumoral glial subgroup located in the brainstem. However, 2 rare groups of brainstem gliomas without histone gene mutations have also been described: the MYCN‐HGG and the silent‐subgroups. The aim of this study was to perform a detailed clinicoradiologic and histomolecular study of MYCN‐HGG of the brainstem.

Methods: A central radiological and pathological review with routine biomarkers assessment was performed. FISH analysis of MYCN and whole exome sequencing on cryopreserved tissue were also performed.

Results: All 6 tumors presented as a nodular mass with annular enhancement on MRI. These tumors were morphologically poorly differentiated with spindle cells. They did not express H3K27M, Lin28A, or BCOR. No loss of H3K27me3, INI1 and BRG1 were observed. The immunohistochemical pattern showed no or focal expression of glial markers (GFAP and Olig2) and a constant expression of at least one neuronal marker. Four tumors overexpressed p53. All tumors presented with an amplification of MYCN and ID2 genes. FISH analysis confirmed the presence of a MYCN amplification in 4/6 cases.

Conclusion: we described detailed clinicoradiologic and immuno‐morphologic features of 6 cases of pontine MYCN‐HGG, thereby highlighting the consistent amplification of MYCN and ID2 genes. This diagnosis must be considered when microscopic features reveal a highly malignant undifferentiated tumor without loss of H3K27me3 trimethylation. Distinguishing this rare neoplasm from diffuse midline glioma, H3K27M‐mutant might allow for establishing targeted molecular therapies in the future.

Symposium 11: S11‐1

Pathological and biochemical changes of tissue deposited amyloid protein by liver transplantation in hereditary ATTR amyloidosis patients

Masahide Yazaki

Institute for Biomedical Sciences, Shinshu University

Hereditary ATTR amyloidosis (familial amyloid polyneuropathy, FAP) is one of the most prevalent systemic amyloidoses caused by mutation of the transthyretin (TTR) gene. Several systemic organs are affected by amyloid accumulation, including the peripheral nerves, heart, eye, and GI tract. As the majority of TTR (over 95%) in the body is produced in the liver, therapeutic liver transplantation has been performed since 1990. While this increased survival paradoxical amyloid deposition occurred in other several organs, including the heart, eye, and central nervous systems (CNS), even after liver transplantation. Our previous study revealed that progression of amyloid cardiomyopathy was due to paradoxical post‐transplant wild‐type TTR deposition produced by the transplanted liver. Amyloid oculopathy and cerebral amyloid angiopathy are serious de novo complications in liver‐transplant patients with FAP. However, the precise pathomechanism of post‐transplantation ocular and CNS amyloid formation is not fully understood. Recently, we biochemically investigated amyloid fibril proteins using laser‐microdissection and LC‐MS/MS and evaluated the composition proportions of wild‐type and variant TTR in amyloid fibrils. In this symposium, we describe the difference in biochemical amyloid proportions and the pathogenesis of amyloid formation between cardiac and ocular/CNS amyloids. Unfortunately, our results suggest that amyloid oculopathy and cerebral amyloid angiopathy cannot be prevented by liver transplantation and will therefore, require other therapeutic options.

S11‐2

Diverse spectrum of hereditary ATTR amyloidosis: polyneuropathy, cardiomyopathy, and cerebral amyloid angiopathy

Taro Yamashita; Mitsuharu Ueda; Yukio Ando

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University

Hereditary transthyretin (ATTRm) amyloidosis (familial amyloid polyneuropathy: FAP) is a life‐threatening, systemic amyloidosis caused by mutant transthyretin (TTR). In addition to ATTR V30M in endemic and non‐endemic areas, more than 140 non‐V30M mutations occur worldwide. The clinical manifestations include length‐dependent sensorimotor polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and familial oculoleptomeningeal amyloidosis (LMA)/hereditary cerebral amyloid angiopathy (CAA), with various degrees of amyloidogenesis and patterns of amyloid deposition. Patients with ATTR V30M in endemic areas shows autonomic‐sensorimotor polyneuropathy at a relatively young age (<50 years old), and patients with ATTR V30M in non‐endemic areas demonstrate large‐fiver polyneuropathy relatively late. Patients with non‐V30M ATTR shows FAP, FAC, or LMS/ CAA. Since mutated TTR is mainly produced by the liver, liver transplantation has become an acceptable treatment for patients with ATTR V30M of early onset. Patients with ATTR Y114C develop LMA and CAA presenting fatal cerebral hemorrhage and rapidly progressive dementia. Postmortem examinations revealed that TTR amyloid deposition in the leptomenges and the blood vessels of the cerebral parenchyma in the transplant patients were tend to be milder compared with those in the non‐transplant patients. However, some patients with ATTR Y114C developed slowly progressive dementia even after liver transplantations. Liver transplantation is partially effective for CNS manifestations of CAA associated with ATTR Y114C reducing mutated TTR in the blood. However, continuing amyloid fibril formation from TTR produced by the choroid plexus and/or wild‐type TTR produced by the transplanted liver might have caused the slowly progression of CAA after liver transplantations.

S11‐3

Pathology of familial amyloid polyneuropathy

Haruki Koike

Department of Neurology, Nagoya University Graduate School of Medicine

Hereditary (variant) transthyretin (ATTRv) amyloidosis, traditionally referred to as familial amyloid polyneuropathy (FAP), is a disease in which systemic deposition of amyloidogenic mutant TTR protein causes multi‐organ failure. Although Val30Met is the most common mutation in FAP, over 130 other mutations have been reported thus far. The dissociation of TTR tetramers is a crucial step in the formation of amyloid fibrils. The process of amyloid formation in FAP has been well investigated in vitro, and a therapeutic strategy to stabilize TTR tetramers in the plasma is now available in clinical practice. However, the in vivo mechanisms of tissue damage resulting from mutant TTR have not been fully elucidated. Although some studies highlight the toxicity of pre‐fibrillar TTR (i.e., the precursor of amyloid fibrils), the amyloid deposits are more widely believed to exert harmful effects on neighboring tissues. Previous studies have demonstrated differences in the morphology of amyloid fibrils in FAP patients with the Val30Met mutation depending on the age at onset. In Japanese FAP patients with the Val30Met mutation, long and thick amyloid fibrils are common in early‐onset cases from endemic foci, whereas the fibrils are usually short and thin in late‐onset cases from non‐endemic areas. As the neuropathic features and modality of the nerve fiber loss in these two forms of FAP are distinct, the difference in the morphology of the amyloid fibrils may be strongly related to the mechanisms of its neuropathy.

S11‐4

Transthyretin Amyloidosis (ATTR)

Merrill D. Benson

Pathology & Laboratory Medicine, Indiana University School of Medicine

Transthyretin amyloidosis (ATTR) was originally called Familial Amyloidotic Polyneuropathy (FAP) and subsequent studies have focused on the pathology of the peripheral nervous system. ATTR, however, is more than that. It is a systemic disease with life threatening manifestations throughout all organ systems including the peripheral nerves, autonomic nerves, CNS, and eye as well as the heart and gastrointestinal tract. Until recently there has been no specific therapy for treatment of ATTR except liver transplantation for patients with hereditary ATTR (FAP). Unfortunately ATTR can progress after liver transplantation due to synthesis of amyloid from wild type TTR. Now a phase 3 study testing a transthyretin specific antisense oligonucleotide for the treatment of patients with ATTR has shown very significant inhibition of disease progression.A study with siRNA to TTR, which is based on the same principle of inhibiting liver TTR synthesis, has also shown significant inhibition of ATTR progression. In addition to the studies on ATTR neuropathy we are now conducting an open label ASO treatment of ATTR cardiomyopathy patients, both hereditary and wild type, to determine safety and tolerability of the ASO in patients with advanced cardiac failure. To date, results have been encouraging with no serious safety issues and with efficacy parameters indicating significant inhibition of progression of cardiomyopathy over a time span from 1 to 4 years.

Symposium 12: S12‐1

Overview of protein propagation in neurodegeneration

Tetsuaki Arai

Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba

Intracellular accumulation of abnormal proteins is the features of many neurodegenerative diseases, including Alzheimer's disease, Lewy body disease and frontotemporal lobar degeneration (FTLD). Recently, these diseases are pathologically classified by the major accumulated proteins such as tau, alpha‐synuclein and TDP‐43, which are collectively referred to as tauopathy, synucleinopathy and TDP‐43 proteinopathy, respectively. Abnormal phosphorylation, ubiquitination, and proteolytic cleavage are the common pathologic signature of these proteins accumulated in diseased brains. Especially, the band patterns of C‐terminal fragments of tau and TDP‐43 on immunoblotting are associated with the clinicopathological features of FTLD‐tau or FTLD‐TDP. Recent research results of the biochemical analyses of the diseased brains and the cellular models suggest that different strains of these proteins with different conformations may determine the clinicopathological phenotypes of these proteinopathies, like prion disease. Detecting each protein strain in biological fluids may be useful for the differential diagnosis of proteinopathies. Furthermore, elucidating the mechanism of the conformational changes leading to the formation of multiple protein strains may be important for developing disease‐modifying therapy for these diseases. For instance, therapeutic strategies targeting the cell to cell propagation of abnormal proteins using antibodies may be useful as novel disease‐modifying therapy of proteinopathies.

S12‐2

Histopathologic Subtypes of FTLD‐TDP: Implications for propagation in neurodegeneration

Edward B lee

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

Most cases of FTLD‐TDP can be subtyped into one of several histopathologic patterns based on the morphology and distribution of TDP‐43 inclusions. The FTLD‐TDP subtypes strongly correlate with several clinical and genetic features of disease. We recently described a series of FTLD‐TDP cases which were difficult to classify based on existing criteria. TDP‐43 aggregates were found in a wide neuroanatomic distribution consisting of ubiquitin‐negative granulofilamentous neuronal inclusions and abundant neuropil grains. Clinically, these cases were associated with very rapid clinical courses with disease duration within three years of symptom onset. We propose that these cases represent a new subtype of FTLD‐TDP (type E). Ongoing work reveals that human FTLD‐TDP brain derived lysates induce TPD‐43 pathology when microinjected into TDP‐43 transgenic mice brains, supporting the protein propagation hypothesis for neurodegenerative diseases. The relationship between histopathologic FTLD‐TDP subtypes and induction of TDP‐43 pathology in experimental models will be discussed.

S12‐3

Systemic propagation of alpha‐ synuclein in the human body

Renpei Sengoku

Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Aggregated alpha‐synuclein (aSyn) in characteristic Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, so‐called Lewy body disease. Recent studies revealed that Lewy related pathology appears not only in the central nervous system but also in the peripheral nervous system especially the autonomic nervous system and enteric nervous system. aSyn represents the primary pathology rather than a consequence on neurodegeneration. Therefore, in order to elucidate the spread of aSyn, it is quite important to investigate the whole body of a Parkinson's disease patient pathologically. We investigated the occurrence frequency and distribution of aggregated aSyn related pathology using the consecutive autopsy patients from the Brain Bank for Ageing Research. Based on the latest our findings and knowledge obtained from animal experiments and human studies about propagation of aSyn, we provide there are several progression pathways such as a pathway from the olfactory to the amygdala.

S12‐4

Prion‐like propagation of pathological tau in neurodegenerative diseases

Masato Hasegawa^1,2

¹Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science; ²Department of Biological Science, Tokyo Metropolitan University

Abnormal tau pathologies are the defining features of many neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Immunocytochemical and biochemical studies revealed widespread phosphorylated tau pathologies in these diseases, and the distributions and spread of these abnormal tau were closely correlated with clinical presentation and disease progression. In adult human brains, six tau isoforms are expressed, and they are classified to four‐repeat (4R) tau and three‐repeat (3R) tau. Tau is a highly soluble, natively unfolded protein, however, in these diseased brains, it is accumulated as filamentous inclusions in abnormally phosphorylated and partially ubiquitinated states. It is demonstrated that the conformations of the abnormal tau in these diseases are distinct between the diseases. Recent studies also have shown pathological tau proteins from brains of patients may have a prion‐like activity that can convert normal tau into an abnormal form. Therefore, we prepared synthetic tau fibrils and sarkosyl‐insoluble pellets of tauopathy brains and investigated the prion‐like seeding activities using culture cell models and injection to wild‐type mouse brains. Both synthetic tau fibrils and sarkosyl pellets of diseased brains showed prion‐like seeding activities in these cellular and animal models. The results suggest that pathological fibrillar forms of tau have prion‐like properties and propagate from cell to cell in brains of patients.

Oral 9: O9‐1

The UCLA brain tumor bank: a comprehensive approach including autopsies, sGluc‐GFP xenografts and ethnic diversity

William H Yong¹; Robert M Prins²; Richard G Everson²; Won Kim²; Harry V Vinters^1,3; Albert M Lai³; Phioanh L Nghiemphu³; Timothy F Cloughesy³; Linda M Liau²; David A Nathanson⁴

¹Dept of Pathology (Neuropathology), UCLA School of Medicine; ²Dept of Neurosurgery, UCLA School of Medicine; ³Dept of Neurology (Neuro‐oncology), UCLA School of Medicine; ⁴Dept of Molecular and Medical Pharmacology, UCLA School of Medicine

Introduction: The incidence of glioblastoma in U.S. non‐Latino Whites is higher than in Latinos who in turn have a higher incidence than Asians or African‐Americans. Latinos have lower rates of gross total resection and radiation, yet have better survival. IDH1 and MGMT status are not different from non‐Latino Whites. As Latinos are a large minority population, understanding their GBM biology and therapy is particularly important.

Methods: Consents are available in English and Spanish. Neuropathologists and on call‐technicians procure blood, surgical tissue and autopsy brains from glioma patients, mostly GBM patients. For surgical specimens, we routinely introduce a lentiviral reporter, secreted Gaussia luciferase tagged to GFP (sGLUC‐GFP), into live tumor cells and then generate glioma patient derived orthotopic xenografts (glioma PDOX).

Results: Tumor burden is accurately measured by serial blood sGLUC‐GFP measurements without need of MRI imaging. These glioma PDOXs preserve the diversity of genetic, transcriptional and immunohistochemical signatures, and are useful for testing therapies. There are over 100 autopsies and over 70 xenografts representing mostly Whites but also Latinos and other minorities. Glioma autopsies can provide data on the evolutionary endpoint of the patient's GBM.

Conclusion: As most procured tumors are from non‐Latino White patients, efforts are being made to recruit more minority patients. Other countries may have unique minorities that do not have GBM biology identical to the majority and that are worth considering for recruitment and study.

O9‐2

mTORC2‐dependent metabolic reprogramming facilitates epigenetic regulation of iron trafficking in glioblastoma

Kenta Masui¹; Paul S Mischel²; Noriyuki Shibata¹

¹Department of Pathology, Tokyo Women's Medical University; ²Ludwig Institute for Cancer Research, UCSD

Introduction: Hyper‐activated growth factor receptor signaling, frequently observed in cancer, reprograms cellular metabolism and global gene transcription, but the underlying mechanisms are not well clarified. Here, we endeavored to examine the role of glycolytic metabolism in the regulation of epigenetics in glioblastoma (GBM).

Methods: To unravel the functional consequences of cancer metabolic reprogramming on epigenetics, we interrogated cell lines, mouse tumor models, and clinical samples of GBM, the highly lethal malignant brain tumor in human.

Results: mTORC2 (mechanistic target of rapamycin complex 2) signaling facilitated acetyl‐CoA production as well as nuclear translocation of histone modifying enzymes including PDH (pyruvate dehydrogenase) and class IIa HDACs (histone deacetylases), resulting in histone H3 acetylation of the ferritin promoter, maintenance of iron trafficking and cancer cell survival. In clinical human samples, mTORC2 signaling was highly correlated with histone acetylation and elevated ferritin expression, indicating mTORC2‐dependent epigenetic regulation of iron metabolism in GBM patients.

Conclusion: In GBM, mTORC2 integrates aberrant growth factor receptor signaling and cellular metabolism with reprogramming of epigenetic landscapes, which drives tumor growth through H3 acetylation in the promoter of iron trafficking genes to promote iron metabolism for tumor cell survival.

O9‐3

Identification of novel gene fusions in glioblastomas with chromothripsis

Audrey Rousseau^1,2; Blandine Boisselier^1,2; Philippe Guardiola^2,3; Emmanuel Garcion²; Philippe Menei^2,4; Franck Ah‐Pine¹

¹Departement de Pathologie Cellulaire et Tissulaire, CHU Angers, Angers, France; ²CRCINA, INSERM, Universite de Nantes, Universite Angers, Angers, France; ³SERGOH, CHU Angers, Angers, France; ⁴Departement de Neurochirurgie, CHU Angers, Angers, France

Introduction: Glioblastoma (GBM), the most aggressive form of glioma, harbors chromosome instability. Chromothripsis (CT) is a cataclysmic event whereby massive chromosome shattering occurs during a single mitotic event. A single or a few chromosomes are shattered and then randomly reassembled in a derivative chromosome. This one‐step event may lead to the inactivation of tumor suppressor genes, the activation of oncogenes and/or the generation of oncogenic fusion genes. CT might underlie the development of GBM and accelerate disease progression. The aim of our study was to identify novel fusion genes in a cohort of GBM harboring CT.

Methods: 280 GBM were previously analyzed by SNP array to detect CT. RNA sequencing (RNAseq) was performed in cases with CT patterns, leading to the identification of candidate fusion genes in CT regions. Gene fusions were confirmed by RT‐PCR followed by Sanger sequencing.

Results: SNP array analysis showed CT patterns in 90 GBM (32%). RNAseq was performed in 32 cases displaying 50 candidate fusion genes in CT regions. RT‐PCR followed by Sanger sequencing confirmed the presence of novel in‐frame fusions, involving key oncogenes such as EGFR, MDM2 and MET but also genes (VOPP1, HMGA2, SEC61G) with yet‐to‐discover role in GBM pathogenesis.

Conclusion: The occurrence of CT points to underlying gene fusions in GBM. Such fusions may drive tumor cell proliferation and survival and may represent therapeutic targets. Our results provide new perspectives to better understand GBM pathogenesis and treat this fatal disease.

O9‐4

Haemangioblastoma and other vascular changes; clinical pathological and immunohistochemical approaches. Clinical, pathological and immunohistochemical approaches

Martha Lilia Tena‐Suck¹; Leora Velasquez‐Perez²; Carlos Sanchez‐Garibay¹

¹Department of Neuropathology, National Institute of Neurology and Neurosurgery; ²Epidemiology Service. National Institute of Neurology and Neurosurgery

Introduction: Haemangioblastoma is a tumor of the CNS that originate from blood vessels and usually through middle‐age.

Methods: This work was a clinic pathological and immunohistochemistry approaches of haemangioblastoma with special emphasis with other vascular changes like, arteriovenous malformations, fibromuscular dysplasia and bigger vessels what we call them as call them as vascular anomalies.

Results: 46 cases were included in this study. 24(52%) females and 22(48%) male, patient history of VHLD in 13(28.3%) and familial history of VHLD in 22 (48%). Histological type was; cellular pattern 20 (46%) and reticular pattern 26(57%), gross vessel was observed a weak or scares in 28(61%) and moderate in 18(39%), in addition. Those gross vessels were observed with Masson and reticulin stain. Vessels anomalies were observed in VHLD than sporadic tumors and in recurrence. Nuclear pleomorphism, nuclear cytoplasmic inclusions, cytoplasmic vacuolation are noted in the stromal cells, and higher Ki67‐li that were in tumor whit vessels anomalies than tumors with VA, and were positive for inhibin A, CD56, vimentin, INI‐1, and VEGF, HIF α, CD56, NSE, Syn, CgA, EMA, exrin, aquaporin, and brachyury. There was not statistical significance with different antibodies used.

Conclusion: Recent data indicate that VHL‐associated hemangioblastoma neoplastic cells originate from embryologically‐arrested hemangioblasts capable of blood and endothelial cell differentiation as well as alterations of the vascular wall. We could say that it is a stromal stem cell tumor in a varied stage of differentiation.

Symposium 13(Collaboration with JSDR Endorsed by AANP): S13‐1

Epidemiology of clinically‐diagnosed dementia in a Japanese community: the Hisayama study

Tomoyuki Ohara^1,2; Toshiharu Ninomiya²

¹Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University; ²Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University

A population based prospective cohort study of dementia has been conducted in an elderly population of the town of Hisayama in the southern part of Japan since 1985.

To examine secular trends in the prevalence of clinically‐diagnosed dementia and its subtypes, five cross‐sectional surveys were conducted among Hisayama residents aged 65 years or older in 1985, 1992, 1998, 2005, and 2012. We conducted a two‐stage screening survey of dementia at each examination, and the diagnosis of dementia was made clinically based on the DSM‐III criteria in 1985 and the DSM‐III‐R in 1992, 1998, 2005, and 2012. The age‐ and sex‐adjusted prevalence of all‐cause dementia increased significantly from 1985 to 2012. With regard to subtypes of dementia, a similar significant trend was observed for Alzheimer's disease (AD), while the prevalence of vascular dementia (VaD) did not change with time.

In a prospective study of risk factors for clinically‐diagnosed dementia conducted in Hisayama elder residents without dementia, diabetes and blood pressure variability in late‐life were a significant risk factor for the development of all‐cause dementia, AD, and VaD. In addition, smokers in both midlife and late‐life had significantly greater risks of AD and VaD than non‐smoker.

In addition to the rapid aging of the population, secular changes in risk factors may be partly responsible for these increasing trends in the prevalence of dementia, especially AD, in the Japanese elderly.

S13‐2

Trends in dementia prevalence over 31 years of the Hisayama study

Hiroyuki Honda

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University

Introduction: In Japan, dementia has become a serious social problem. The Hisayama study is a prospective cohort study of lifestyle‐related diseases including dementia that was started in 1961. In the population‐based study, it has been reported that all‐cause dementia and Alzheimer's disease (AD) significantly increased in recent years.

Methods: The aim of this study is to clarify the trends in dementia using data from 1371 autopsied performed over the past 31 years (1986‐2016). Throughout the whole period, the autopsy rate is about 75%. We divided the 1371 autopsy samples into five groups according to the year of death: I (1986‐1991, 257 cases), II (1992‐1997, 268 cases), III (1998‐2004, 318 cases), IV (2005‐2011, 296 cases), and V (2012‐2016, 232 cases). In addition, we investigated the increases in brain pathology related to AD using automated morphometric analyses for quantifying tau pathology.

Results: The prevalence of all‐cause and AD significantly increased. A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD‐NFT) in recent years was notable. The morphometric analyses revealed a significant increasing of tau pathology in recent years. The significance was also observed regardless of the senile plaques.

Conclusion: We revealed a recent trend of increased tauopathy such as AD and SD‐NFT, which is partly independent of amyloid‐beta pathology. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases.

S13‐3

Independence and interdependence of neuritic amyloid plaques, neurofibrillary tangles, striatal A‐beta, hippocampal abnormalities, and generalized brain atrophy as elements of Alzheimer's disease

Lon R. White

University of Hawaii and the Pacific Health Research and Education Institute, Honolulu

Concurrent neuritic amyloid plaques (NAP), neurofibrillary tangles (NFT), and generalized brain atrophy were recognized by Alzheimer himself in his reports of premature senility. While this triad remains central to diagnosis of Alzheimer's disease (AD) even today, the underlying mechanisms responsible for their mutual associations remain largely obscure. This uncertainty and the recognition of very high rates of multi‐morbidity identifiable at autopsy represent challenges for correct diagnoses and recognition of pre‐clinical disease during of life. Although an association of the ApoE epsilon 4 allele with the accumulation of neocortical neuritic plaques is well established, its independent associations with NFT, striatal amyloid, hippocampal and neocortical neuronal loss, and gliosis are less certain. Our analyses of data from the Honolulu‐Asia Aging Study (Japanese‐American men) and the Nun Study (Caucasian women) indicate that each of these elements appears to occur and influence cognitive impairment at least partially independently of the others. Nonetheless their full impact on cognition is apparent only when they are simultaneously present. Similar patterns of occurrence and associations with dementia are evident in both studies. These observations indicate a complex pathogenesis of AD and suggest the possible importance of interventions aimed simultaneously at the separate determinants which may exist for these three distinct neuropathologic elements.

S13‐4

The Rush Community Studies of Aging with Autopsy ‐ Highlights and Implications

Julie A. Schneider; David A Bennett; Lisa L Barnes; Patricia A Boyle; Zoe Arvanitakis; Sue E Leurgans; Robert s Wilson

Rush Alzheimer's disease center/Neurology, Rush University Medical Center

Background: The Rush Community Studies including the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Minority Aging Research Study (MARS) are ongoing longitudinal clinicopathologic cohort studies of aging and Alzheimers disease (AD).

OBJECTIVES: To provide highlights and implications of the Rush community autopsy studies.

Methods: Participants are older adults who enroll without dementia and agree to longitudinal clinical evaluations. Agreement to organ donation is required in ROS and MAP and is optional in MARS.

Results: Rush clinicopathologic studies have shown that there is remarkable heterogeneity in brain pathologies of elders. AD pathology is rarely the sole pathology in elders with Alzheimers dementia while it is common in persons without cognitive impairment. Most persons with an Alzheimers dementia have AD pathology with additional neurodegenerative (lewy bodies, TDP43, hippocampal sclerosis) and, or vascular (infarcts, vessel diseases) pathologies. There are multiple individual combinations of these pathologies in any one person and overall these pathologies account for less than half of the variability of cognitive decline in aging. These and other data show it is imperative to study amyloid and tau but also to investigate multiple other pathologies. In addition to targeting individual pathologies for treatment, approaches should aim at upstream biologic factors, final common pathways, and mechanisms of resilience.

Conclusion: Longitudinal cliniconeuropathologic studies in community dwelling older persons have strongly contributed to a transformation in the current thinking of AD and related disorders, resulting in promising new research directions toward prevention, detection, and treatment.

S13‐5

Overview of Japan semisupercentenarian study

Nobuyoshi Hirose, Yasumichi Arai, Takashi Sasaki

Center for Supercentenarian Medical Research, Keio University School of Medicine

We are conducting centenarian study from 2000. At the initial phase, the target of our study is centenarian in Tokyo area(Tokyo Centenarian Study: TCS). Then we started longitudinal Japan semisupercentenarian study (JSS) from 2002 till now. The target of JSS was semisupercentenarian (105+; SSC) in whole area of Japan. Now target of JSS is shifting from SSC to supercentenarian(110+; SC).The object of centenarian study is, 1) to identify the factors associated with happy and healthy longevity, 2) to understand the phenotype of ultimate human aging.We use multidisciplinary approach for the study of centenarian, such as medical, genetic and psychological domain.The number of centenarian in Japan are increasing more than exponentially from 153 in 1963 to 67,824 in 2017.However, number of SC is only 146 in 2015. They are extremely rare ( 1 in 870,000 total population). ADL and cognitive function of SC at 100 years old is excellent compared with younger centenarians. And genetic make‐up is also different from younger centenarians.Based on these findings, we think that SC is a real model of healthy longevity. In this presentation, we will briefly summarize the results of TCS and JSS. Then we will present characteristics of supercentenarian. Prof Takao will present the autopsy finding of SC. We think that SC study is fascinating and rewarding. We hope young scientists will actively participate SC study.

S13‐6

Brain pathology of supercentenarians

Masaki Takao

International Medical Center, Saitama Medical University

Following the presentation by Professor Hirose, I would like to some information of brain pathology of supercentenarians. Since we had previously reported four autopsy cases of SC brains (Acta Neuropathol Commun. 2016; 97), we obtained three additional SC autopsy cases. All seven cases were of Japanese female and their mean age of death was 111.2 years old (111‐114). The numbers of cases for each phase of Thal's A‐beta were as follows: 1 in three, 2 in one, 3 in two and 4 in one cases; of neuritic plaque score (CERAD) were none in 2 and moderate in 5 cases and of Braak NFT stage were III in four and IV in three cases. There were four intermediate and three low level cases based on the NIA‐AA criteria for AD. Three low level cases were consistent with PART possible (Braak NFT stage III or IV, A‐beta Thal phase 1or 2). Aging‐related tau astrogliopathy was consistently observed, particularly in the basal forebrain. Neither Lewy bodies nor glial cytoplasmic inclusion were observed. We believe that the neuropathologic changes of SC is not simple pre‐pathologic condition of AD. Future studies of SC brains are needed to understand the process of aging.

Symposium 14: S14‐1

What's going on in the field of veterinary neuropathology

Hiroyuki Nakayama

Veterinary Pathology, The University of Tokyo

Rodent species such as mice and rats have been used as model animals to study human diseases. However, there are too much evolutional distance between human and rodents. Ungulata such as cows, sheep, pigs and horses, and Carnivora such as dogs and cats, which are evolutionally located between human and rodents, can be used as model animals to fill in the gap of the missing link of revolution. We are studying neuropathology of nonhuman animals under the concept of evolutional medicine. Some topics in the field of veterinary neuropathology like “Aging‐related brain changes and neurodegenerative disorders in animals”, “Possibly immune‐mediated encephalomyelitis in dogs” and “Brain tumors in animals” will be introduced in the session.

S14‐2

Encephalomyelitis in dogs

Kazuyuki Uchida

Veterinary Pathology, the University of Tokyo

In dogs, most typical encephalomyelitis is caused by canine distemper virus (CDV) infections characterized by subacute to chronic demyelinating encephalomyelitis. The pathologic features of CVD‐associated encephalomyelitis are almost in conformity with those of human measles virus infections. Besides, necrotizing meningoencephalitis (NME) and granulomatous meningoencephalitis (GME) are idiopathic inflammatory diseases of the canine brains and are more commonly found in veterinary clinics in Japan. Typical NME occurs predominantly in Pug dogs. Recent molecular investigations have identified possible genetic risk factors for NME in Pug dogs. NME is characterized pathologically by necrotic lesions with lymphocytic infiltration in the meninges and perivascular spaces. On the basis of the distribution pattern of major necrotic foci, NME can be divided into cortex dominant and white matter dominant types; the latter is designated necrotizing leukoencephalitis (NLE) predominately found in Yorkshire terrier dogs. Lesions in GME are characterized by the accumulation of lymphocytes and macrophages with epithelioid morphology, forming granulomas around blood vessels. Some common genetic factors and/or some additional triggers, such as infection or vaccination, may play a role in the pathogenesis of NME, NLE and GME; however, the host immune responses may define the pathological phenotypes. Different cytokine and chemokine responses are seen in NME, NLE and GME, whilst autoantibodies against astrocytes are detected predominantly in NME. The pathological and immunological characteristics of these canine idiopathic inflammatory brain disorders are focused on the presentation.

S14‐3

Aging‐related brain changes and neurodegenerative disorders in animals

James Chambers

Veterinary Pathology, the University of Tokyo

Comparative neuropathology provides new insights on the pathogenesis of neurodegenerative diseases. As for age‐related sporadic neurodegenerative diseases such as Alzheimer's disease, there are variations with the lesions that are observed in the brains of different animal species. Unlike other mammalian species, aged felids (domestic cat, leopard cat and cheetah) develop neurofibrillary tangles (NFT) comparable to that of human. Interestingly, these species do not form mature senile plaques, instead small granular amyloid‐beta deposits are observed in individuals with NFT. Senile plaques and amyloid angiopathy are frequently observed in other mammalian species such as monkeys and dogs, although rodents do not show amyloid‐beta deposits due to difference in amino acid sequence of amyloid‐beta protein. Lesions associated with Parkinson's disease and amyotrophic lateral sclerosis (ALS) have not been widely examined in animal species. Mutation of the SOD1 gene has been identified in dogs with degenerative myelopathy that shows some similarity to ALS. As for inherited neurodegenerative diseases, counterparts of the human diseases have been found mostly in household pets. Mutation of the corresponding genes have been identified together with histological changes comparable to that of human disease. Here, we would like to share some of the pathological findings of animal cases of Lafora disease, Alexander disease, globoid cell leukodystrophy, neuroaxonal dystrophy and ceroid lipofuscinosis. For neurodegenerative diseases caused by alteration of a specific gene, non‐rodent animal models may be valuable for future translational clinical trials.

S14‐4

Brain tumors in animals

Takuya Evan Kishimoto; Kazuyuki Uchida; James K. Chambers; Hiroyuki Nakayama

Veterinary Pathology, the University of Tokyo

Primary brain tumors are relatively rare in domestic animal species with the exception of dogs and, to a lesser extent, of cats. The incidence of each tumor type differs among species, as well as among breeds or strains within a species. There is a relatively high incidence of meningiomas in cats, while gliomas are most prevalent in dogs. Within the canine species, short‐nosed (brachycephalic) breeds such as Boxers and Bulldogs are predisposed toward gliomas, while long‐nosed (dolichocephalic) breeds such as Collies and German shepherds tend to develop meningiomas. In addition, French bulldogs are the breed with a common onset of oligodendroglioma. In our study, over a half of glioma cases in dogs are observed in French bulldogs, and most of the French bulldog cases were anaplastic oligodendroglioma (over 90%). We have demonstrated histological and immunohistochemical characteristics of canine oligodendroglioma and have established a cell line from an original tumor. Canine oligodendroglioma bears striking similarities to its human counterpart. Moreover, as described in human, canine oligodendroglioma highly expresses oligodendrocyte precursor cell (OPC) markers such as nuclear transcription factors Olig2 and SOX10, platelet‐derived growth factor receptor a (PDGFRa) and proteoglycan NG2. These results suggest that canine oligodendroglioma may be a suitable animal model for a comparative study on human oligodendroglioma.

Educational Lecture: EL

The WHO 2016 CNS Tumor Scheme: A summary and perspective

Arie Perry

Department of Pathology, Division of Neuropathology, University of California, San Francisco (UCSF)

The WHO 2016 classification scheme and more recent advances have resulted in major diagnostic shifts for diffuse gliomas, a subset of ependymomas, and embryonal neoplasms. The new approach focuses on the integrated diagnosis, which incorporates classic histopathology with specific molecular signatures. A number of surrogate immunohistochemical (IHC) stains are now also available for identifying biologically distinct molecular subtypes. The most common division is that of the IDH‐mutant diffuse gliomas from their biologically more aggressive IDH‐wildtype counterparts. Other examples include histone H3 mutations in the diagnosis of diffuse midline gliomas (K27M mutation) and pediatric glioblastomas (G34R/V mutations), as well as the identification of a more aggressive supratentorial ependymomas defined by RELA fusion (L1CAM positive) and posterior fossa B ependymomas (loss of H3K27me3 staining). Also, in diffuse astrocytomas, the majority of IDH‐mutant and H3 G34‐mutant cases additionally show loss of ATRX expression and strong p53 staining, serving as clues for further molecular testing as needed. Oligodendrogliomas still require detection of 1p/19q codeletion by molecular testing in addition to IDH mutation, although the vast majority of these can be predicted ahead of time based on the combination of classic histology with retained ATRX expression and negligible p53 expression. In the case of medulloblastoma subtyping, a number of WNT and SHH surrogate stains are available, whereas other IHC markers may be useful for identification of embryonal tumor with multilayered rosettes (LIN28), atypical teratoid/rhabdoid tumor (INI1, BRG1), and high‐grade neuroepithelial tumor with BCOR alteration (BCOR).

Special Lecture 3: SL3

Methylation Profiling for Precision Diagnosis of Human Brain Tumors

Andreas von Deimling

Department of Neuropathology and Clinical Cooperation Unit Neuropathology, University Heidelberg and German Cancer Research Center DKFZ

The WHO 2016 diagnostic approach to human brain tumors relies on morphological evaluation, immunohistochemistry and molecular tests focally targeting tumor specific alterations. Testing is mostly based on variations of FISH and DNA sequencing approaches. In a joint effort, teams in Heidelberg have explored the feasibility of different omics platforms for the classification of human brain tumors. Most stable throughout tumor progression proved methylome data, while genome and transcriptome data experience considerable change within an individual tumor. Therefore, we have established a classification system for brain tumors based on genome wide promoter methylation status.

2801 human tumor tissues forming a comprehensive reference group have been subjected to methylome analysis using 450K/850K‐EPIC chips from Illumina. Unsupervised clustering or t‐SNE analyses have been employed to identify methylation clusters. A tool named “the classifier” employing random decision forests has been developed and is updated on a regular schedule. The brain tumor classifier in its current version recognizes more than 80 different methylation groups. Approximately 5% of the tumors analyzed do not match to these groups and are expected to eventually be recognized as independent tumor entities pheno‐copying established entities. In fact, several novel brain tumor entities have recently been identified mainly on grounds of their characteristic and unique methylation profile. The classifier is accessible to researchers at www.molecularneuropathology.com.

Within four years of testing the classifier has evolved an indispensable tool for the analysis of brain tumors in the Heidelberg research and diagnostic environment. Currently many diagnostic institutions are implementing the classifier because methylome based classification of human brain tumors adds decisively to the precision of diagnosis.

Symposium 15: S15‐1

Novel, improved grading system for IDH‐mutant astrocytomas

Mitsuaki Shirahata¹; Takahiro Ono²; Damian Stichel⁴; Daniel Schrimpf^3,4; David E. Reuss^3,4; Felix Sahm^3,4; Christian Koelsche^3,4; Annika Wefers^3,4; Annekathrin Reinhardt^3,4; Kristin Huang^3,4; Philipp Sievers^3,4; Hiroshi Nanjo⁸; Atsushi Sasaki⁷; Hiroaki Shimizu²; Ryo Nishikawa¹; David Capper⁵; Andrey Korshunov^3,4; David N. Louis⁶; Andreas von Deimling^3,4

¹Department of Neurosurgery/Neurooncology, Saitama Medical University International Medical Center; ²Department of Neurosurgery, Akita University, Japan; ³Department of Neuropathology, Heidelberg University, Germany; ⁴Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, Germany; ⁵Department of Neuropathology, Charite University, Germany; ⁶Department of Pathology, Massachusetts General Hospital, USA; ⁷Department of Pathology, Saitama Medical University International Medical Center; ⁸Division of Clinical Pathology, Akita University Hospital, Akita, Japan

IDH‐mutant astrocytomas comprise a wide range of malignancies, and patients’ survival times vary from less than two years to over twenty years. The framework of grading was not updated in the WHO 2016 classification, and recent studies have demonstrated that the anticipated diferences in survival between the IDH‐mutant astrocytoma Grade2 and Grade3 have lost their signifcance. However, the idea of simply classifying such tumors exhibiting various survival times into two groups, such as glioblastoma and lower grade glioma, would be a clinically too rough classification. A new grading approach specialized in IDH‐mutant astrocytoma is required. We undertook a comprehensive analysis assessing both morphological and molecular factors to establish a novel grading model associated with patients’ outcome. A discovery cohort of 211 IDH‐mutant astrocytomas was subjected to histological review, image analysis, and illumina 450k/850k array analysis. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major infuence were necrosis and the total number of CNV. Importantly, tumors haboring CDKN2A/B homozygous deletion showed worse survival compared to the tumors haboring necrosis which is the hallmark pathological feature of glioblastoma.Employing CDKN2A/B homozygous deletion, necrosis and total number of CNV which were found to be most relevant for OS in our discovery set, we developed two grading models. The prognostic predictability of the models was validated in three independent cohorts of 108, 154 and 224 IDH‐mutant astrocytomas. We propose that CDKN2A/B status, together with presence of necrosis, should be incorporated into a future grading framework for IDH‐mutant astrocytomas.

S15‐2

A mathematical model for predicting the optimal timing of treatment to minimize the malignant transformation rate in WHO grade II diffuse glioma

Kousuke Aoki¹; Kazuya Motomura¹; Hideo Nakamura²; Yoshitaka Narita³; Koji Yoshimoto⁴; Yasutomo Momii⁵; Yoshihiro Muragaki⁶; Toshihiko Wakabayashi¹; Hiroshi Haeno⁷; Atsushi Natsume¹

¹Department of Neurosurgery, Nagoya University School of Medicine; ²Department of Neurosurgery, Kumamoto University; ³Department of Neurosurgery and Neuro‐oncology, National Cancer Center; ⁴Department of Neurosurgery, Graduate School of Medical Science Kyushu University; ⁵Department of Neurosurgery, Oita University; ⁶Department of Neurosurgery, Tokyo Women's Medical University, Mathematical Biology Laboratory; ⁷Department of Biology, Kyushu University

In WHO grade II diffuse gliomas (low‐grade gliomas, hereafter called LGGs), chemotherapy and radiotherapy contribute to prolonged survival but could induce somatic mutations. The optimal timing of treatment in LGGs remain poorly understood. To delineate this, we propose a mathematical model for tumor growth and investigate the association among the treatment, the accumulation of somatic mutations, and malignant transformation (MT) in LGGs. Totally, 201 patients with LGGs between 1990 and 2014 were analyzed. We assessed the statuses of IDH mutation and 1p19q co‐deletion in all tumors. Among all, 78 patients (39%) underwent MT during follow‐up periods (mean: 78months). Tumor volume was evaluated with FLAIR and/or T2‐weighted MR imaging. MT was evaluated with contrast‐enhanced MRI and/or pathological diagnosis. Oligodendroglioma, IDH‐mutant and 1p/19q‐codeleted (OD) showed longer transformation‐free survival compared to other subtypes. The growth rates and the risk of MT increased after surgery in OD and Diffuse astrocytoma, IDH‐mutant (DA). They significantly decreased in the middle of chemotherapy but returned to the same as before when chemotherapy ended. Based on growth rate and the risk of MT, optimal timing of treatments was calculated for each genetic subtype. Early surgical resection could minimize the risk of MT only if the tumors were totally resected. Early radiotherapy and chemotherapy could reduce the risk of MT, if limited resection were performed in OD and DA, respectively. In other cases, adjuvant therapy could be waited. The mathematical model delineates the optimal timing of treatments in each subtype, which will help to decide the treatment for LGGs.

S15‐3

Preoperative design of the treatment strategy for lower grade gliomas based on molecular diagnosis by imaging features

Hikaru Sasaki; Tokunori Kanazawa; Kazunari Yoshida

Department of Neurosurgery, Keio University School of Medicine

In WHO 2016, the lower grade gliomas (LrGGs) are classified based on IDH and 1p/19q status, and this classification correlates well with clinical outcomes. Since 2006, we have been treating the patients with LrGGs with 1p/19q codeletion or MGMT promoter methylation by upfront chemotherapy. The median volume change by chemotherapy in cases of initial incomplete resection (partial removal or biopsy) was ‐30‐35% (SPD), and upfront chemotherapy enabled second‐look resection to be performed following tumor volume decrease in many cases (J Neurooncol 124(1):127‐35, 2015). However, molecular information relevant to treatment strategy is available only after tumor resection. If it is informed before initial surgery, such information could influence the initial surgical strategy as well as overall treatment strategy. To preoperatively predict tumor molecular status, we have established the scoring system to predict 1p/19q codeletion based on imaging features available on routine CT and MRI (Neurosurg Rev 2018 Apr 26). Quantitative texture analysis using commercially available software also showed high positive predictive value. Indeed, treatment strategy for some of the recent patients with 1p/19q‐codeleted gliomas were preoperatively designed based on molecular diagnosis by imaging, including intentional staged operation and intentional placement of BCNU wafers. Molecular diagnosis based on imaging information would help to preoperatively design personalized treatment in patients with LrGGs.

S15‐4

PI3 kinase pathway activation to promote malignant progression in oligodendroglial tumor

Kensuke Tateishi¹; Taishi Nakamura¹; Shigeta Miyake¹; Yuko Matsushita²; Yohei Miyake¹; Shoji Yamanaka⁴; Tetsuya Yamamoto¹; Kochi Ichimura²; Hiroaki Wakimoto²; Cahill Daniel²

¹Department of Neurosurgery, Yokohama City University, Yokohama, Japan; ²Division of Brain Tumor Translational Research, National Cancer Center Institute, Tokyo, Japan; ³Department of Pathology, Yokohama City University Hospital, Yokohama, Japan; ⁴Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, NY; ⁵Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

Oligodendroglioma (OD) is a subtype of diffuse astrocytic and oligodendroglial tumors. Although prognosis in OD tumors are initially favorable, majority of OD develop malignant transformation. Therefore, understanding of molecular mechanism is crucial to identify therapeutic target. However, there are few available patient‐derived OD xenograft model, which limits preclinical investigations. Here, we present novel patient derived anaplastic oligodendroglioma (AOD) xenograft models. We have harvested two distinct cell samples with and without PIK3CA mutation. From PIK3CA mutant cells with rapid progression, we established xenograft model, while xenograft was not formed from PIK3CA wild‐type cells, which was not developed malignant transformation. We confirmed AOD phenotype and the presence of IDH1 mutation and 1p/19q co‐deletion in xenograft tissue, indicating recapitulating AOD model. We also tested to see if PI3K/AKT/mTOR gene mutation could induce patient‐derived AOD xenograft formation. As expected, whereas no tertiary mutant tumor did not form xenograft, PI3K/AKT/mTOR mutant AOD cells formed xenograft. Also, we found such mutant tumor cells were vulnerable to alkylating agents and PIK/AKT/mTOR pathway inhibitors. These findings suggested the critical role of PI3K/AKT/mTOR pathway activation for xenograft formation in oligodendroglial tumors. Our xenograft models may allow figure out detailed mechanism for malignant transformation, which will contribute to identify optimal therapeutic strategy.

S15‐5

7‐tesla MR susceptibility‐weighted imaging can dipict astrocytic and oligodendroglial pathology

Manabu Natsumeda¹; Hitoshi Matsuzawa²; Yoshihiro Tsukamoto¹; Kunio Motohashi^1,2; Yu Kanemaru^1,3; Kouichirou Okamoto¹; Akiyoshi Kakita¹; Hironaka Igarashi²; Tsutomu Nakata²; Yukihiko Fujii¹

¹Department of Neurosurgery, Brain Resaerch Institute, Niigata University, Niigata, Japan; ²Department of Neurosurgery, Brain Resaerch Institute, Niigata University; ³Department of Pathology, Brain Resaerch Institute, Niigata University

Background: There are very few reports of ultrahigh field 7‐tesla magnetic resonance susceptibility weighted imaging (7T‐SWI) used in the diagnosis of brain tumors. In the present study, we performed 7T‐SWI on glioma patients to distinguish between astrocytic and oligodendroglial tumors.

Methods: Sixteen patients pathologically diagnosed as gliomas who underwent presurgical 7T‐MR imaging were included. We used a 7T MR imager (General Electric) and obtained high resolution T2‐weighted two‐dimensional Fast Spin Echo (FSE) images and T2* weighted, two dimensional gradient echo (2D‐GRE) images. SWI post‐processing was performed using in‐house software written in MATLAB (Math Works, Natick, MA, USA). The gliomas were pathologically diagnosed according to the 2016 WHO classification, and IDH mutations were detected by IDH1 R132H as well as Sanger sequencing and 1p/19 LOH was detected by Multiplex Ligation‐dependent Probe Amplification (MLPA) analysis. SWI images were scored as astrocytic‐like or oligodendroglial‐like based on scoring system accounting for cortical thickening and shift of medullary vessels (minimum ‐2 to maximum +2).

Results: Ten cases were diagnosed as astrocytomas (WHO grade 2 to 4) and 6 cases as oligodendrogliomas (WHO grade 2 or 3). Cortical thickening and shift of medullary vessels were seen in oligodendrogliomas, whereas medullary vessels were not shifted in astrocytomas, suggesting an infiltrative nature. Scoring was significantly elevated in oligodendrogliomas (p= 0.0057; astrocytomas mean ‐0.9 vs. oligodendrogliomas 1.5). Microbleeding, necrosis, and thickening of medullary veins were seen in malignant cases.

Conclusion: 7T‐SWI could reliably distinguish between astrocytomas and oligodendrogliomas and predict malignancy. SWI accurately reflected the vascular morphology of gliomas.

Poster Session 2: P2‐1

Neuronal loss and progression of Alzheimer's disease related pathology observed in a Swedish patient with clinical diagnosis of idiopathic normal pressure hydrocephalus

Sylwia Libard^1,2; Katarina Laurell³; Kristina Giuliana Cesarini⁴; Irina Alafuzoff^1,2

¹Department of Immunology, Genetics and Pathology, Uppsala University; ²Department of Pathology, Uppsala University Hospital; ³Department of Pharmacology and Clinical Neuroscience, Ostersund, Umea University; ⁴Department of Neuroscience, Neurosurgery, Uppsala University

Introduction: Here we assessed changes observed in neuronal population, inflammation and hallmark lesions of Alzheimer’s disease(AD) occurring during 21 months, in one subject with AD and idiopathic normal pressure hydrocephalus(iNPH).

Clinical summary: 63 years old woman debuted with cognitive impairment in 2005. Two years later she was clinically diagnosed with AD and iNPH. Her symptoms progressed rapidly and liquor dynamics test led to ventriculoperitoneal shunt insertion. Cortical biopsy was taken during the shunt operation in 2010. She improved postoperatively in motor function and alertness. The patient passed away 21 months after shunt‐surgery and a neuropathological assessment of the brain was performed.

Pathological findings: The cortical biopsy and the post‐mortem brain displayed AD pathology. Morphometrically assessed immunoreactivity showed increase in hyperphosphorylated τ(HPτ) and amyloid‐β(Aβ)40 paralleled with decrease of Aβ42, neuronal markers (synaptophysin, microtubule associated protein 2, non‐phosphorylated neurofilament H, embryonic lethal abnormal visual system proteins 3/4 HuC/HuD) and microglial markers (CD68, Human Leucocytic Antigen DR, ionized calcium‐binding adaptor molecule 1). Glial fibrillary acidic protein and total Aβ were stable. Around the shunt‐channel minor tissue damage with reactive changes was seen.

Conclusion: In a patient with iNPH and end‐stage AD, progression of HPτ pathology, neuronal loss, decrease in expression of Aβ42 and microglial markers were observed. The tissue damage near the shunt‐channel was negligible. Post mortem neuropathological evaluation of the brain of previously biopsied patients with iNPH is recommended.

P2‐2

Effects of systemic infection on the brain in the late stage of Alzheimer's disease

Sonja Rakic¹; Clive Holmes^1,2; Seth Love³; William Stewart⁴; James AR Nicoll^1,5; Delphine Boche¹

¹Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United‐Kingdom; ²Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United‐Kingdom; ³Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Southmead Hospital, Bristol, United‐Kingdom; ⁴Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom; ⁵Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, United‐Kingdom

Introduction: Clinical studies indicate that systemic infection/inflammation may contribute to and accelerate Alzheimer's disease (AD). Animal models suggest that this may be due to enhanced proinflammatory changes in the brain.

Methods: Cerebral tissue from controls and AD patients who died with systemic infection (16Ctrl; 40AD) or without (24Ctrl; 28AD) was immunolabelled and quantified for Aβ, phosphorylated (p)tau and several neuroinflammatory proteins. In AD, synaptic proteins were assessed by ELISA, and inflammation/related proteins and mRNA were measured by Multiplex Assays and qPCR.

Results: Systemic infection did not modify Aβ, ptau or the synaptic proteins. In AD with systemic infection, there was increased IL6 and decreased IL5, IL7, IL12/IL23p40, IL15, IL16 and IL17A, associated with elevated expression of immunosuppressive genes (CHI3L1 and IL4R). This was related with decreased CD16 (grey matter) and CD68 (white matter) antigen loads, and increased CD64 (white matter). In AD without systemic infection, CD68, CD64, CHI3L1, IL4R and CCR2 (grey matter) were increased, and CD32a (white matter) was decreased. Associations (p<0.001) were observed between grey and white matter Iba1 (motility) in the controls without systemic infection; CD68 (phagocytosis) and CCR2 (myeloid recruitment) in AD without systemic infection; and CD64 (immunoglobulins) in both cohorts but with systemic infection only.

Conclusion: Our findings suggest that terminal systemic infections modify AD neuroinflammation, apparently by promoting an immunosuppressive environment in the brain. This highlights that microglia have a complex role in both promoting and responding to the neurodegeneration.

P2‐3

The pathological characteristics of neuronal Apolipoprotein E in normal aged controls and AD brains

Ito Kawakami; Eloise Hudry; Alberto Serrano Pozo; Bradley T. Hyman

Dept. of Neurology, Massachusetts General Hospital, Harvard Medical School

Introduction: APOE‐ε4 risk allele is well known to be the genetic factor for late onset Alzheimer disease(AD). Previous studies have suggested that APOE‐ε4 increases amyloid β accumulation in human brains. However, the role in tau pathology remains uncertain.

Methods: We investigated the distribution of intraneuronal apoE in hippocampus and temporal/occipital neocortex of normal aged controls and compared the results to pathologically confirmed AD cases with several APOE genotypes. In addition, we examined the colocalization of apoE and neurofibrillary tangles (NFT) to find out the role of apoE in tau pathology.

Results: In control cases, we observed consistent and widespread apoE intraneuronal staining in hippocampus, especially higher in CA1 region. They showed moderate staining in the cortexes. AD brains displayed the milder immunoreactivity in hippocampus but lower in the cortexes, compared to control cases. ApoE antibodies labels various stages of neurons, including neurons without NFT, pre‐tangle, and ghost tangle. APOE‐ε4 carriers demonstrate lower apoE in neurons than other AD groups. As for tau pathology, the ratio of apoE in NFTs decreased as ε4 allele copy number increases.

Conclusions: We assume that apoE has a neuroprotective role in control brains and APOE‐ε4 has an influence on acceleration of tau pathology in AD.

P2‐4

Deep phenotyping and multi‐omics analysis of a homogeneous sample of familiar Alzheimers disease brains

Diego Sepulveda‐Falla^1,2; Robert Haesler³; Laura Heikaus⁴; Christoph Krisp⁴; Claudio Mastronardi⁵; Francisco Lopera²; Mauricio Arcos‐Burgos⁵; Hartmut Schlueter⁴; Markus Glatzel¹

¹Institute of Neuropathology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany; ²Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellin, Colombia; ³Institute of Clinical Molecular Biology, Christian‐Albrechts‐University, Kiel, Germany; ⁴Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany; ⁵Institute of Translational Medicine, University of el Rosario, Bogota, Colombia.

Introduction: Familial Alzheimers disease (FAD) is often considered as the optimal study model for this disease. FAD is characterized by early dementia onset and severe neuropathology. We have been following up the largest cohort in the world suffering from FAD, comprising 1100 PS1E280A carriers. Despite their common background, PS1E280A patients present wide clinical variability. In this study we explore the association of clinical and pathological phenotypes with high‐throughput data analysis.

Methods: 23 PS1E280A postmortem brains were selected for biochemical and histological studies based on quality of the samples. Studies included A4 and Tau pathology characterization, wide exome scan, RNA sequencing and LS/MS analysis. Patients were grouped according to clinical or pathological features and multivariate, principal component and clustering analyses were performed for genomic, transcriptomic and proteomic data.

Results: We found association of clinical features, such as disease duration or age of onset of dementia, with specific pathological and biochemical profiles for Tau pathology, kinases and protein degradation networks. Furthermore, we have identified association between specific cognitive profiles and protein networks not directly linked to amyloid beta or Tau pathology.

Conclusion: Even in a genetically uniform sample with a clear etiology for AD it is possible to identify other pathological processes and biological variants that have a direct effect in disease presentation. The application of deep phenotyping and multi‐omics analysis in neurodegenerative diseases promises to be a valid approach for identifying other biological processes that could act as disease modifiers and will assist in the design of better targeted therapies.

P2‐5

Supranuclear ophthalmoplegia, neck dorsiflexion, and midbrain tegmentum atrophy associated with brainstem pathology of Alzheimer's disease in Japan

Naoki Kasahata^1,3,5; Hiroyuki Kato²; Mariko Hagiwara¹; Yoshihisa Makita⁴; Toshiki Uchihara^5,6,7

¹Division of Neurology, Department of Medicine, Tokyo Metropolitan Ohtsuka Hospital; ²Department of Laboratory Medicine, Tokyo Metropolitan Ohtsuka Hospital; ³Department of Neurology, Makita General Hospital; ⁴Department of Pathology, Makita General Hospital; ⁵Laboratory of Structrual Neuropathology, Tokyo Metropolitan Institute of Medical Science; ⁶Department of Neurology and Neurological Science, Tokyo Medical and Dental University; ⁷Department of Neurology, Nitobe Memorial Nakano General Hospital

Introduction: It has been well known that Alzheimer's disease affect brainstem, however, clinical manifestation caused by brainstem involvement have not been elucidated. We encountered 2 cases presented supranuclear ophthalmoplegia, neck dorsiflexion, and midbrain tegmentum atrophy associated with barinstem pathology of Alzheimer's disease.

Clinical summary: Case 1 A 75‐year‐old man developed 9 years course of l‐dopa nonresponsive parkinsonism, supranuclear ophthalmoplegia, and neck dorsiflexion at the terminal stage. MRI revealed atrophy of the midbrain tegmentum. Case 2 An 85‐year‐old man developed 9 years course of l‐dopa responsive parkinsonism and subsequent dementia, followed by supranuclear ophthalmoplegia, neck dorsiflexion, and dementia. MRI revealed midbrain tegmentum and medial temporal lobe atrophy.

Pathological findings: Case 1 Cortical atrophy was moderate in frontal and temporal lobes. the substantia nigra and locus coeruleus were depigmented. Abundant senile plaques were detected in cerebral cortex (Braak C) and frequently detected in colliculi. Neurofibrillary tangles were positive for both 3R and 4R tau with the predominance of 3R tau. They were abundant in cerebral cortex (Braak VI), and frequent in colliculi. Lewy bodies were abundant in amygdala. Case 2 Substantia nigra showed thin but depigmentation was mild. Locus coeruleus showed depigmentation. Microscopic findings demonstrated pure Alzheimer's disease (tangle pathology: Braak V, plaque pathology: Braak C) with 3R dominant neurofibrillary tangles in substantia nigra, near riMLF, and superior colliculus. Senile plaques showed in superior colliculus. Neither Lewy body nor α‐synculein positive material were observed.

Conclusion: Alzheimer's pathology affect brainstem, which can cause supranuclear ophthalmoplegia, neck dorisflexion, and atrophy of midbrain tegmentum.

P2‐6

Wnt signaling molecules are involved in the formation of rimmed vacuoles and granulovacuolar degeneration bodies

Tetsuya Takahashi¹; Yukari Murata‐Shinozaki¹; Tomoyasu Matsubara¹; Yuishin Izumi²; Hirofumi Maruyama¹

¹Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences; ²Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima

Introduction: Previously, we have demonstrated that rimmed vacuoles (RVs) and granulovacuolar degeneration (GVD) bodies are immunopositive for a set of common molecules suggesting that both RVs and GVD bodies originate from similar structures on the plasma membrane of muscle cells and neuronal cells, i.e. the neuromuscular junction (NMJ) and the postsynaptic spine especially in terms of Wnt signaling pathway.

Methods: We investigated the presence of components of NMJ in RVs and/or postsynaptic spine in GVD bodies immunohistochemically. The tested molecules are as follows; (1) dishevelled (Dvl) family proteins, (2) NMJ associated proteins (low density lipoprotein related protein 4:Lrp4, heat shock protein 70:Hsp70, β‐catenin, phospho β‐catenin, rapsyn, P21 activated kinase 1:PAK1, adenomatous polyposis coli;APC and ADP ribosylation factor 6;Arf6), (3) a lipid raft‐associated molecule (phosphatidylinositol 4, 5 bisphosphate:PIP2), and (4) other proteins;prion, glycogen synthase kinase 3β:GSK3β.

Results: In all cases of sporadic inclusion body myositis examined, RVs were immunopositive for Dvl3, Hsp70, β‐catenin, PIP2, APC, prion and GSK3β. In all cases of Alzheimer disease examined, GVD bodies were immunopositive for Dvl3, phospho β‐catenin, rapsyn, APC and PIP2.

Conclusion: RVs and GVD bodies share common molecules associated with the Wnt signaling pathway, indicating that these structures share a common structural and functional origin.

P2‐7

Early tau pathology in young Japanese forensic autopsy series: Frequency and association with APOE genotype and suicidal risk

Koji Yoshida^1,2; Yukiko Hata³; Hideo Terasawa¹; Hirotaka Shimizu¹; Toshiyuki Uehara¹; Yuji Nakatsuji²; Yasushi Kita¹; Naoki Nishida³

¹Department of Neurology, Hyogo brain and heart center; ²Department of Neurology, Toyama University Hospital; ³Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

Introduction: Early tau pathology of Alzheimer's disease (ET) observed in brainstem such as locus ceruleus and raphe nuclei in young people are not known in detail. We aimed to reveal the demographic, genetic and clinical aspects of ET with Japanese forensic autopsies.

Methods: From a total of 1614 serial Japanese forensic autopsy cases, we detected the cases under 40 years of age. ET and senile plaques were assessed with Braak stages and Thal grade following immunohistochemistry. Genomic DNA was isolated from whole blood, and APOE was genotyped by Sanger sequencing.

Results: We assessed 187 cases (mean age 25.5±13.0 years, 125 males, 62 females, 0‐39 years) and detected ET in 102 cases (54.5%, 13‐39 years). ET was not related to sex and APOE genotype. Relatively high stage of ET (1a stage and over) cases showed significantly low suicide rate.

Conclusion: ET was high frequency in young Japanese, and had no relation to sex and APOE genotype. Tau pathology may not be a significant accelerating factor for suicide in the early pathological phase.

P2‐8

Neuron‐specific histone modification analysis of Alzheimer's disease brains

Kagari Mano¹; Tatsuo Mano¹; Atsushi Iwata¹; Shigeo Murayama²; Tatsushi Toda^1,2

¹The University of Tokyo; ²Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: To elucidate the pathomechanism of sporadic neurodegeneration, patients’ brains are the most essential resources. However, they are vulnerable to postmortem degradation, that compromises precise analysis. Furthermore, they are composed of varieties of cells making difficult to extract neuron‐specific information. To overcome these issues, we conducted neuronal histone modification analysis using fluorescent activated cell sorting (FACS) combined with chromatin immunoprecipitation (ChIP) and next‐generation sequencing (NGS) to indirectly assess neuronal gene expression.

Methods: We examined the postmortem brain samples from eight sporadic AD patients and eight age‐matched normal controls (NC). Neuronal nuclei were isolated from brain tissues using FACS and subjected to ChIP‐Seq with anti‐H3K4me3 antibody which is known to be bound to active promotor regions. The differentially bound regions between the two groups were searched using DiffBind.

Results: We detected two differentially bound regions (GENE A, B) between the two groups with false discovery rate (FDR) < 0.05. In GENE A, AD showed lower H3K4me3 methylation level of the transcription starting sites (TSS). In GENE B, AD showed higher H3K4me3 methylation level of the TSS. Indeed, immunostaining and western blotting consistently showed a significant reduction of protein A expression. Protein A is known to be associated with perineuronal nets formation.

Conclusions: We performed neuron‐specific ChIP‐seq and found a novel gene associated with sporadic AD. The result indicated usefulness of neuronal ChIP‐Seq using postmortem brain when studying sporadic neurodegeneration.

P2‐9

A Japanese pedigree of Alzheimer's disease with novel presenilin 1 mutation Try215Arg and amyloid angiopathy. A report of three cases

Shinobu Kawakatsu^1,2; Ryota Kobayashi²; Hiroshi Hayashi²; Takeshi Ikeuchi³; Koichi Otani²

¹Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University; ²Department of Psychiatry, Yamagata University School of Medicine; ³Department of Molecular Genetics, Brain Research Institute, Niigata University

Introduction: Although 227 mutations in presenilin 1 (PSEN1) have been reported, clinicopathological study of several Alzheimer's disease (AD) cases in the same pedigree is limited. We described clinicopathological findings of 3 AD cases with PSEN1 Try215Arg mutation in the same family.

Methods and Results: In this pedigree, 14 individuals over 4 generations were affected and three cases went to autopsy. The mean age of onset was 50 years and that of death was 61 years. Novel PSEN1 mutation Try215Arg was identified in 3 three cases. Patient 1 became amnestic at the age 46 years. Next 10 years, her dementia progressed and muscle rigidity was noted. She died at the age 60. The brain weighed 860g. Patient 2 became forgetful at the age 44 years. At 46 years, MMSE scored 16, and apraxia and visual agnosia were noted. MRI showed diffuse cortical atrophy and white matter hyperintensities. SPECT revealed parietal hypoperfusion. She died at the age 55. The brain weighed 860g. Patient 3 became forgetful and apathetic at the age 48 years. MRI at the age 56 showed diffuse cortical atrophy including hippocampus. CT scan at the age 59 revealed occipital and thalamic intracerebral hemorrhage. She died at the age 60. The brain weighed 790g. All three patients had amyloid angiopathy (AA) as well as abundant tangles and prominent amyloid depositions including cerebellum. There were no cotton wool plaques.

Conclusion: AA was characteristics of PSEN1 Try215Arg mutation but the degree of AA displayed a variability in the same pedigree.

P2‐10

The first autopsy case of Alzheimer disease after treatment of anti‐amyloid beta antibody (solanezumab)

Yasuto Higashi¹; Shigeo Murayama²

¹Division of Neurology, Himeji Central Hospital; ²Department of Neurology and Neuropathology (the Brain Bank for Aging Research)

Introduction: We here report the first autopsy case of Alzheimer disease (AD) after treatment of solanezumab.

Clinical summary: A sixty‐ year old man came to our clinic with complaint of forgetfulness. Neurological examination was unremarkable and MMSE was 21/30. MRI and FDG PET revealed cerebral atrophy and hypometabolism, consistent with AD. He participated double blind clinical trial of solanezmab for one and a half years and then open trial of active drug for three years. His decline of mental state did not ameliorate and at age 66, he admitted to our hospital for BPSD. Two weeks later, he died of aspiration pneumonia. The interval between the last administration of solanezumab and death was one month.

Pathological findings: Neuropathologially, the brain weighed 1250 g. Gross examination was unremarkable. Histologically, Rraak neurofibrillary tangle stage was 6, CERAD stage for senile plaque was C and Thal's amyloid stage was 5. Unique pathology of A beta included focal wiped out of senile plaques with preserved tangles in the left amygdala, in addition to multifocal moth‐ eaten‐ like disappearance of amyloid. Mild amyloid angiopathy was present.

Conclusion: These pathological features mimic the result of active immunization of A beta. This case may indicate the effectiveness of passive immunotherapy to remove A beta but not tau from brains with AD.

P2‐11

Amyloid precursor protein plaque‐like structures in late‐onset Alzheimer disease

J Provias¹; S Jevitic²

¹Department of Pathology & Molecular Medicine, McMaster University, Hamilton Health Sciences, Hamilton General Site, Hamilton, ON, Canada; ²Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada

Introduction: Amyloid‐beta (Aβ) peptide, derived from the amyloid precursor protein (APP), has been viewed as a central contributor to Alzheimer Disease (AD) pathogenesis for many years. Many therapeutics have been developed that reduce Aβ load in patients but, to date, have all failed in clinical trials. To this end, we present a novel focus on APP as a pathological contributor in AD through investigation of various cases involving late‐onset Alzheimer Disease (LOAD).

Clinical summary: 6 cases of LOAD were identified through neuropathological evaluation of Aβ and tau, age of onset, and reported family history. Generally cases had clinical signs of dementia; one case was included involving no history of dementia. Cases involving additional pathology (e.g. alpha‐synuclein) were excluded.

Pathological findings: In addition to typical AD pathologic changes, interestingly, many of these cases demonstrate unique “plaque‐like” and granular structures of APP that are separate from Aβ plaques. These structures appear extracellularly and bear resemblance to dystrophic neurites with no association to tau neurites (potentially preceding their development). We suggest that local accumulations of APP in plaque‐like/neuritic‐like aggregates, are involved in the pathogenesis of other AD changes, preceding tau, possibly contributing to tau dystrophic neurite formation.

Conclusion: Based on the neuropathologic observations of human AD cases, it is hypothesized that APP may play an active role in the development of other AD tau and beta amyloid pathology, beyond being just a passive player in the genesis of beta amyloid plaques.

P2‐12

Distribution of different forms of Aβ in the brain of subjects with Alzheimer's disease, MCI and intact cognition

MA Riudavets^1,5; O Pletnikova¹; S Resnick³; G Rudow²; R Obrien^2,4; Yang An³; G Sevlever⁵; M Schultz⁵; JC Troncoso^1,2

¹Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine. Baltimore, Maryland, USA; ²Department of Neurology, Johns Hopkins University School of Medicine. Baltimore, Maryland, USA; ³Intramural Research Program, National Institute on Aging. Baltimore, Maryland, USA; ⁴Department of Neurology, Duke University School of Medicine. Durham, North Carolina, USA; ⁵Department of Neuropathology, Institute for Neurological Research, FLENI. Buenos Aires, Argentina

Introduction: The diagnosis of AD dementia is based on clinical evaluation of the patient, but requires postmortem neuropathologic confirmation for definitive diagnosis. Advances in neuroimaging tools such as amyloid imaging radiotracers for PET scanning, raise the possibility of confirming the diagnosis of AD in the living patient. The clinical utilization of PET imaging has heightened the need for rigorous imaging‐pathological correlations in AD in the brains of subjects in various cognitive states.

Methods: We performed immunostains for Aβ (6E10) and pyr‐Aβ (pyrE3), and Thioflavin‐S stains in cortical and subcortical structures of 28 subjects from the Baltimore Longitudinal Study of Aging, including AD, MCI, asymptomatic‐AD, and controls.

Results: Total Aβ burden, compared between the AD and control groups, was significantly different for most brain regions. Aβ burden in AD subjects showed significant differences for the thalamus. Pyr‐Aβ form displayed the same distribution of Aβ detected using 6E10 antibody; however, with more marked deposition in neocortical regions. Effect sizes for differences between AD and controls in the amount of Aβ plaques –measured with Thioflavin‐S‐ were largest in entorhinal cortex, entorhinal‐hippocampus cluster, and temporal‐entorhinal‐hippocampus cluster.

Conclusion: Our findings using Thioflavin‐S as an Aβ marker showed distributions of pathology comparable to some neuroimaging studies using PET radioligands. Whereas the differences in Aβ deposition between AD and controls are marked with different methodologies and different forms of Aβ (i.e. the toxic form Pyr‐Aβ), the differences are less conspicuous in early stages of the disease, which remain a challenge to both the neuropathologist and neuroimager.

P2‐13

Brain transcriptome analysis of Japanese population living in Brazil

Suely Kazue Nagahashi Marie¹; Antonio Marcondes Lerario⁵; Sueli Mieko Oba Shinjo¹; Camila Nascimento¹; Renata Leite^2,4; Claudia Suemoto^3,4; Carlos Augusto Pasqualucci^3,4; Shigeo Murayama^6,7

¹Departments of Neurology, Faculdade de Medicina, Universidade de Sao Paulo, SP; ²Pathology, Faculdade de Medicina, Universidade de Sao Paulo, SP; ³Internal Medicine, Discipline of Geriatrics, Faculdade de Medicina, Universidade de Sao Paulo, SP; ⁴the Brain Bank of the Brazilian Aging Study Group (BBBASG), Faculdade de Medicina, Universidade de Sao Paulo, SP; ⁵Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan, USA; ⁶Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology (TMGHIG); ⁷Brain Bank for Aging Research (BBAR), Tokyo, Japan

Environment impacts phenotype through epigenetic mechanisms. Comparison of individuals with similar genetic background living in different environmental conditions allows to unveil these mechanisms. We aim to identify targets under epigenetic regulation comparing transcriptome and methylome of brain samples from Japanese living in Japan and Brazil. Here, we present the first phase of this study of twelve Japanese Brazilian cases of the second generation of immigrants (age 47‐95, mean 73.2yo). The neuropathological evaluation according to BBAR protocols classified 3 cases as Braak III Alzheimer Disease (AD), 3 cases as Argyrophilic Grain (AG), 3 cases as Lewy Body (LB), and 3 cases as normal (NC). We performed RNASeq analysis of the amygdala of autopsy specimens to interrogate transcriptional changes associated with these conditions in the Illumina NextSeq. 600 genes were differentially expressed between the conditions and the controls. We used WebGestalt to interrogate biological processes overrepresented in these lists. In AD cases, immune system response (GOID:2376, p = 3.62 × 10⁻⁸), and regulation of cell proliferation (GOID:8284, p = 2.67 × 10⁻⁶) were among the processes most strongly enriched. Among the 65 genes with fold change >4 TACR3, TRAC, CSF3, SLC9A2, IL1B, SELE, IL6, ICAM1, IL32, SERPINA3, CXCL10, IFI44L, HAMP,HMOX1, OPN4, FCGR1B were relevantly connected in network of immune response. In AG cases, genes related to response to stress (GOID: 2952, p = 1.31 × 10⁻⁵) and aminoglycan catabolic process (GOID: 6026, p = 0.0003) were observed. In LB cases, genes related to peptidyl‐glutamine modification (GOID:18199, p = 0.0002) and oxygen transport (GOID:15671, p = 0.001) were detected. Methylome data will be integrated to these transcriptome data and the results compared to the dataset generated with Japanese‐Japanese brain samples.

P2‐14

Cerebral hypoperfusion and Aβ interfere with pericyte trophic signalling pathways in Alzheimer's disease

J Scott Miners¹; Seth Love¹

¹School of Medicine, University of Bristol

Introduction: Pericytes regulate multiple vascular functions. In AD precuneus we previously showed loss of pericytes, indicated by a reduction in the pericyte marker PDGFRB, correlating with markers of reduced oxygenation, and elevated Aβ. We have now explored possible mechanisms.

Methods: PDGFRB and markers of cerebral oxygenation (MAG:PLP1, VEGF) were measured as previously (Miners et al. J Cereb Blood Flow Metab 2018;38:103) in precuneus from 40 AD and 31 control brains. Human brain‐derived pericytes were cultured in 2% oxygen for 72h ± Aβ40 or Aβ42. Pericyte trophic factors and receptors were measured by ELISA.

Results: PDGFRB level correlated positively with markers of better oxygenation (increased MAG:PLP1, decreased VEGF) in controls but not AD. Neither hypoxia nor exogenous Aβ (except at high levels) for 72h caused overt pericyte toxicity, but both reduced pericyte proliferation. Pericyte VEGF level rose in response to hypoxia, but so did VEGFR1 (anti‐proliferative), and VEGFR2 and PDGFRB (both pro‐proliferative) declined. Proliferation of pericytes in response to VEGF, PDGFBB or EDN1 was also inhibited by Aβ. Pericyte expression of Ang1 (pro‐survival) was reduced by Aβ40 (100nM); that of Ang2 (pro‐apoptotic) was elevated by hypoxia and by Aβ42 (100nM).

Conclusions: Hypoxia and Aβ interfere with trophic signalling pathways that regulate pericyte homeostasis. This is likely to block the proliferative response of pericytes to elevated VEGF, PDGFBB and EDN1 in AD, and to cause pericyte dysfunction and loss, as has been demonstrated in the disease. The mechanisms are unclear but may involve Aβ‐mediated sequestration of trophic factors, or receptor inactivation.

P2‐15

Zibotentan, an EDN1A antagonist, prevents Aβ‐induced hypertension, maintains cerebral perfusion, and may have therapeutic potential for Alzheimer's disease

Jen Palmer; Hannah M Tayler; Laurence Dyer; Patrick G Kehoe; Julian F R Paton; Seth Love

School of Medicine, University of Bristol

Introduction: Cerebral blood flow is reduced in patients with Alzheimer's disease (AD). Aβ accumulation, a hallmark of AD, upregulates the cerebral endothelin system. We have investigated whether parenchymal infusion of Aβ40 modulates systemic blood pressure (BP), carotid blood flow and markers of cerebral hypoperfusion in Wistar rats, and also the effects of administering the endothelin‐receptor antagonist zibotentan on Aβ‐induced haemodynamic changes.

Methods: Normotensive 12‐14wk male Wistar rats were assigned to one of four groups Aβ40‐infused not on zibotentan (Aβ‐zib); Aβ40‐infused on zibotentan (Aβ+zib); saline‐zib; and saline+zib. Aβ was infused into the striatum over 28d by mini‐osmotic pump, blood pressure was monitored using an implanted radiotelemetry device, and carotid blood flow was measured by use of electromagnetic flow probes. After completion of the infusions, Aβ level and markers of tissue oxygenation were measured in the brain tissue.

Results: Infusion of Aβ induced a progressive rise in systemic BP. Zibotentan administration abrogated the effects of Aβ infusion on BP, without any adverse effect on carotid blood flow or cerebral oxygenation.

Conclusions: These findings provide further evidence that reduced cerebral perfusion caused by Aβ accumulation may induce mid‐life hypertension. The amelioration of these effects by zibotentan raises the possibility that EDN receptor antagonists may have therapeutic potential in early AD.

P2‐16

Corticobasal syndrome‐Pick's disease with Pick bodies: a clinicopathological study

Yuto Uchida^1,2; Mari Yoshida³; Koji Takada²; Yasukuni Tsugu²; Noriyuki Matsukawa¹

¹Department of Neurology, Nagoya City University Graduate School of Medical Sciences; ²Department of Neurology, Toyokawa City Hospital; ³Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical

Introduction: Corticobasal syndrome (CBS) is characterized by an atypical parkinsonian syndrome with apraxia, and is associated with several distinct histopathologies, including corticobasal degeneration, other forms of tau‐related degeneration such as progressive supranuclear palsy, and Alzheimer disease. However, Pick's disease (PiD), 3‐repeat tauopathy, is rarely included in this clinical entity. We report the clinicopathological finding of a patient with CBS‐PiD, which demonstrated the association between the presenting phenotype of CBS and the distribution of Pick bodies.

Clinical summary: A 80‐year‐old right‐handed man gradually experienced increasing difficulty with speech and skill movement. He had speech of apraxia and right‐limb apraxia with slight extrapyramidal signs, as well as end‐stage dementia.

Pathological findings: Neuropathologically, focal cortical atrophy, neuronal loss, and gliosis were most prominent in the left opercular, precentral and postcentral gyri, and parietal lobes. Bodian's silver stain and 3‐repeat tau immunohistochemistry showed numerous Pick bodies, which were diffusely present in those areas and, to a lesser degree, in the temporal lobes. By contrast, the degeneration in the subcortical gray matter was mild in the substantia nigra, subthalamic nucleus, globus pallidus, and striatum.

Conclusion: This case represents a rare histopathology of CBS, suggesting that the clinical features of PiD have a much wider spectrum than generally assumed. The clinical manifestations are thought to depend on the topographic distribution of Pick bodies, which located intensively to the frontoparietal region instead of the frontotemporal region.

P2‐17

Chronic traumatic encephalopathy and motor neuron disease in a retired football player

Kathy L Newell¹; Bernardino F Ghetti²

¹Dept of Pathology & Laboratory Medicine, University of Kansas School of Medicine, Kansas City, KS, US; ²Dept of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, US

Chronic traumatic encephalopathy (CTE) has been associated with clinical or neuropathologic features of amyotrophic lateral sclerosis. A 66 year‐old former professional football player with a history of 30 concussions during his career was evaluated by a neurologist for weakness of the upper and lower extremities and mild memory loss. Nerve conduction studies showed fasciculations in the extremities and tongue. The clinical impression was motor neuron disease. At age 67, the patient died of respiratory failure. An autopsy was carried out. The brain, 1420 grams, was grossly unremarkable except for a small lacune in the left caudate nucleus and mild depigmentation in the substantia nigra. Histologic sections were stained with Luxol fast blue‐H&E and antibodies to Abeta, ptau, alpha‐synuclein, and pTDP43. The primary motor area showed mild loss of neurons in the lower cortical layers and neuronophagia. The spinal cord anterior horns contained neuronal loss and gliosis. The corticospinal tracts showed no myelin pallor. Tau‐immunopositive inclusions were most numerous in neurons and glia in the entorhinal cortex, hippocampus, amygdala, and temporal neocortex. Multiple foci of ptau‐positive glia were seen perivascularly and in the depths of sulci. Sparse tau‐immunopositive inclusions were detected in the substantia nigra, locus coeruleus, and posterior medulla. pTDP43‐immunopositive inclusions were seen in spinal cord neurons and glia. Frontal cortex contained sparse diffuse Abeta plaques. There was mild Abeta angiopathy. No alpha‐synuclein aggregates were identified. The association of CTE with motor neuron disease raises etiologic questions about chronic traumatic head injury and neurodegeneration.

P2‐18

Aberrant accumulation of ErbB4 in progressive supranuclear palsy and Alzheimer's disease

Aya Murakami¹; Masataka Nakamura¹; Satoshi Kaneko¹; Wen Lang Lin²; Dennis W Dickson²; Hirofumi Kusaka¹

¹Department of Neurology, Kansai Medical University; ²Department of Neuroscience, Mayo Clinic

Aims: The human epidermal growth factor receptor family consists of 4 members that belong to the ErbB lineage of proteins (ErbB1‐4). Neuregulin‐1 (NRG1)/ErbB signaling regulates brain development, synaptic plasticity and neuronal survival. Change in ErbB4 expression levels have been implicated in the etiology or development of neurodegenerative diseases such as Alzheimers disease (AD), Parkinsons disease, and amyotrophic lateral sclerosis. So, we aimed at investigating whether the expression of NRG1 or ErbB proteins is altered in progressive supranuclear palsy (PSP) and AD.

Methods: The brains of 10 PSP, 2 AD and 6 control patients were investigated by immunohistochemical and electron microscopy analysis.

Results: Whereas C‐terminal ErbB4 immunoreacitivity was partially but distinctly present in the cytoplasm and/or in the nucleus of neurons in control patients, it was rarely observed in the neuronal nuclei in PSP and AD patients. In contrast, neurofibrillary tangles in PSP and AD, coiled bodies and threads in PSP were robustly immunoreacive for C‐terminal ErbB4. C‐ErbB4 immunoreacitivity was expressed surrounding neuritic plaques in AD. Double immunofluorescence for C‐terminal ErbB4 and phospho‐tau revealed co‐localization of these proteins within neuronal inclusions in PSP and AD and glial inclusions in PSP. To the contrary, there was no difference in the subcellular localization of NRG1, ErbB1, ErbB2, and N‐terminal ErbB4 between control, PSP, and AD patients. These proteins were localized in the cytoplasm of neurons.

Conclusions: Our present results suggest that decreased NRG1/ErbB4 signal transduction to the nucleus could be an important event in the pathogenesis of PSP and AD.

P2‐19

Glial three repeat tau accumulation in progressive supranuclear palsy

Daisuke Taniguchi¹; Masashi Takanashi²; Taku Hatano¹; Nobutaka Hattori¹

¹Department of Neurology, Juntendo University, School of Medicine; ²Department of Neurology, Juntendo University Koshigaya Hospital

Introduction: PSP is pathologically categorized as a 4‐repeat tauopathy. Small amounts of pathological 3‐repeat tau accumulation have been reported in neurons, whereas there are few reports about 3‐repeat tau in glial cells.

Clinical summary: A Japanese male complained unsteadiness in walking at age 71, and then frequently fell down the next year. He showed levodopa‐unresponsive parkinsonian symptoms adding to supranuclear gaze palsy and frontal lobe dysfunction. He was in bedridden state at age 75. In advanced stage of disease, bilateral vocal cord paralysis, myoclonus, pyramidal signs, and ataxic respiration were observed. He died of aspiration pneumonia at age 84.

Pathological findings: There was severe neuronal loss with gliosis in the brainstem tegmentum, substantia nigra, red nucleus, locus ceruleus, subthalamic nucleus, globus pallidus, dentate nucleus, and precentral cortex. Gallyas‐Braak‐positive and phosphorylated‐tau‐positive tufted astrocytes, coiled bodies, neurofibrillary tangles, and neuropil threads were seen in the above lesions. The neuropathologic criteria for PSP were clearly fulfilled. Notably, these structures were positive for 4‐repeat tau, and many of them including tufted astrocytes were also positive for 3‐repeat tau. Confocal imaging revealed 3‐repeat tau immunoreactivity was superimposed on 4‐repeat tau immunoreactivity in the neurofibrillary tangles and tufted astrocytes. Beta‐amyloid deposits were only seen in hippocampus and putamen. Immunoblot analysis of sarkosyl‐insoluble brain samples showed similar results to PSP. There was no MAPT mutation.

Conclusion: Our case suggested that PSP patient, especially with long clinical course, would have the potential to develop 3‐repeat tau accumulation in glial as well as neuronal cells.

P2‐20

Putaminal Tau Pathology in the Aging Japanese Population: The Hisayama Study

Hideomi Hamasaki¹; Hiroyuki Honda¹; Tsuyoshi Okamoto^2,3; Satoshi O Suzuki¹; Toshiharu Ninomiya⁴; Toru Iwaki¹

¹Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University; ²Faculty of Arts and Science, Kyushu University; ³Graduate School of Systems Life Sciences, Kyushu University; ⁴Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University

Introduction: Hisayama study is a prospective cohort study commenced in 1961 in the town of Hisayama in Fukuoka Prefecture, Japan. In principle, all residents of the town of Hisayama are proposed to be autopsied when they die, and the total autopsy rate is about 75%. We previously reported that Alzheimer's disease (AD) and hippocampal tau deposits were increasing in recent years in Japan. In this study, we extend our observation towards putaminal tau pathology in the aging Japanese population.

Methods: We examined a series of autopsied cases from Hisayama residents obtained between 2009 and 2014 (224 cases). To evaluate tau pathology quantitatively, we performed immunohistochemistry with AT8 antibody and automated quantitative analysis using a platform called MATLAB.

Results: Tau deposits in putamen gradually increased around 70 years of age, and were correlated with the Braak stage. Certain AD cases showed severe tau deposits in putamen. Amyloid deposition in the putamen was not necessarily correlated with the putaminal tau deposition. We subdivided all cases into low CERAD (CERAD score 0‐1) and high CERAD (CERAD score 2‐3) groups to examine the effect of cerebral amyloid deposits on the putaminal tau pathology. The areal mean of putaminal tau deposition was significantly higher in the high CERAD group.

Conclusion: The cases with severe tau deposits in putamen were largely attributed to AD in the aging population.

P2‐21

Staging of brain lesions by phosphorylated tau‐immunohistochemistry in the parkinsonism‐dementia complex and amyotrophic lateral sclerosis of Guam

Kiyomitsu Oyanagi^1,2; Tomoyo Hashimoto³; Mineo Yamazaki⁴; Mitsunori Yamada²; Hitoshi Takahashi⁵; Akiyoshi Kakita⁵

¹Brain Research Laboratory, Hatsuishi Hospital; ²Department of Brain Disease Research, Shinshu University School of Medicine; ³Department of Neurology, University of Occupational and Environmental Health, Fukuoka; ⁴Department of Neurology, Nippon Medical School Chiba Hokusou Hospital; ⁵Department of Pathology, Brain Research Institute, Niigata University

Introduction: Parkinsonism‐dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) had been endemic neurodegenerative diseases in Guam of the western Pacific Ocean. Widespread occurrence of neurofibrillary tangles (NFTs), which are mainly composed of hyper phosphorylated tau, is the neuropathological hallmark of PDC, and relatively small amount of NFTs have been elucidated in patients with ALS and Guamanian non‐PDC non‐ALS control subjects.

Methods: Immunohistochemistry for phosphorylated tau (AT8) was applied to six‐micrometer‐thick formalin‐fixed paraffin‐embedded sections of brains and spinal cords of thirteen Guamanian patients with PDC, nine ALS, five combined with PDC and ALS, and eight controls. The progression pattern and staging of the lesions with AT8‐immnopositive were examined.

Results: NFTs were positive for AT8 immunohistochemistry with rare neuropile threads, and four immunopositive stages were identified. Stage I: Macroscopically negative but a few AT8‐positive NFTs in the temporal cortex or brain stem tegmentum. Stage II: Macroscopically positive slightly in the CA1 and transentorhinal cortex with or without patchy positivity in brainstem tegmentum. Stage III: slightly and diffusely immunopositive involving Ammon's horn, temporal cortex, superior and middle frontal cortex, neostriatum, amygdaloid nucleus, thalamus, hypothalamus, brainstem tegmentum, substaitia nigra and pontine base. Stage IV: strongly immunopositive in every lesions of Stage III and inferior olivary nucleus, and slightly positive in the inferior frontal cortex and orbital cortex.

Conclusion: Staging of brain lesions by phosphorylated tau‐immunohistochemistry in the PDC, ALS and controls was identified four. Differences from Alzheimer's disease are rare neuropile threads and massive progression into brainstem.

P2‐22

Clinicopathological comparison between typical and non‐typical progressive supranuclear palsy

Taku Homma^1,4,5; Yoko Mochizuki^1,6; Makoto Hara²; Hideki Takubo³; Manabu Takahashi⁴; Takashi Komori⁵; Satoshi Kamei²; Hiroyuki Hao¹

¹Department of Human Pathology, Division of Pathology and Microbiology, Nihon University School of Medicine; ²Department of Neurology, Nihon University School of Medicine, Tokyo, Japan; ³Department of Neurology, Ebara Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan; ⁴Department of Pathology, Ebara Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan; ⁵Department of Neuropathology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ⁶Department of Neurology, Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled, Tokyo, Japan

Introduction: Progressive supranuclear palsy (PSP) is one of the major tauopathies, characterized by the presence of tufted astrocytes and globose neurofibrillary tangles (NFT) showing four‐repeat tau immunoreactivity. Clinically, PSP is classified into subtypes, including the PSP‐Richardson syndrome (PSP‐RS), which is considered as typical PSP, and PSP with predominant cerebellar ataxia (PSP‐C). In this study, we examined the clinicopathological differences between PSP‐RS and PSP‐C.

Methods: Seven autopsy‐confirmed PSP cases clinically considered as PSP‐RS (6 cases) and as PSP‐C (1 case) were examined. The degree of neurodegeneration, number of AT8‐positive neurons, and degree of AT8‐positive threads in several target areas were semi‐quantitatively analyzed.

Results: Neurodegeneration was observed in the globus pallidus, subthalamus, and substantia nigra in all 7 cases. Immunohistochemical examination revealed that AT8‐positive neurons and/or AT8‐positive threads were widely present in all cases. In addition, the AT8 pathology of neurons/neuropil was a frequent feature not only in oculomotor nuclei, but also in the hypoglossal nuclei. In the PSP‐C case, neurodegeneration with AT8 pathology was significant in the inferior olivary nuclei, pontine transverse fibers, pontine nuclei, and cerebellar white matter, compared to the PSP‐RS cases.

Conclusion: We found that: 1) AT8 pathology severely affects the cerebellar afferent system of PSP‐C, compared with that of PSP‐RS, and 2) the AT8 pathology of neurons/neuropil was a frequent finding in the hypoglossal nuclei in PSP.

P2‐23

Anti‐iglon5 syndrome: a new entity at the crossroads of neurodegeneration and neuroimmunology

Lei Liu¹; Yueshan Piao²; Jiawei Wang^1,3

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Pathology, Xuanwu Hospital, Capital Medical University; ³Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: Since 2014, less than 30 patients have been described with a novel neurological syndrome characterized by parasomnia with sleep breathing disorder, accompanied by bulbar symptoms and specific IgG against the neuronal cell adhesion protein IgLON5. Autopsy showed neuronal loss, gliosis, extensive deposits of hyperphosphorylated tau, but absence of inflammatory infiltrates. The 3 and 4 repeat tau mainly involves hypothalamus and from tegmentum of the brainstem down to the upper cervical cord.

Methods: Case report and in vitro indirect immunofluorescence tissue based assay.

Results: A 59‐year‐old man was presented for admission after 6 months of parasomnia and 2 months of diplopia. His past medical history included dizziness and gait instability for two years. Brain MRI was unremarkable. Polysomonographic study showed frequent obstructive sleep apneic events with moderate oxyhemoglobin desaturations. Movement resembling manipulating objectives during sleep were also recorded. Laboratory evaluations only showed high titers of anti‐IgLON5‐IgG in both serum and CSF. He also carried specific HLA alleles, which are iconic in this syndrome. Immunoreactivity of patient's sample was a pattern of diffuse neural synaptic more intense in the cerebellum (granular layer more than molecular layer) than in the hippocampus.

Conclusion: Although hyperphosphorylated repeat tau confine to certain area in autopsy study, anti‐IgLON5‐IgG reacts with the whole neuropil in vitro. This mismatch may lead to further investigations of pathophysiological mechanism and anatomical susceptibility of this syndrome.

P2‐24

Pathological validation study of corticobasal degeneration. An interim progress report of Japanese validation study of CBD (J‐VAC study)

M. Yoshida¹; T. Komori²; Y. Saito³; K. Wakabayashi⁴; S. Murayama⁵; K. Hasegawa⁶; A. Kakita⁷; O. Yokota⁸; I. Aiba⁹; K. Nakashima¹⁰

¹Dpt. of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University; ²Dpt. of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital; ³Dpt. of Pathology and Laboratory Medicine, National Center Hospital of Neurology and Psychiatry; ⁴Dpt. of Neuropathology, Hirosaki University Graduate School of Medicine; ⁵Dpt. of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ⁶Dpt. of Neurology, NHO, Sagamihara National Hospital; ⁷Dpt. of Pathology, Brain Research Institute, Niigata University; ⁸Dpt. of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; ⁹Dpt. of Neurology, National Hospital Oganization (NHO), Higashinagoya National Hospital; ¹⁰Dpt. of Neurology, NHO, Matsue Medical Center, Japan

Introduction: Corticobasal degeneration (CBD) is a sporadic neurodegenerative disorder characterized by progressive levodopa‐nonresponsive rigidity with focal cortical signs, such as apraxia and aphasia, and often dementia of the frontal type. The expanding understanding of CBD indicate the wide range of clinicopathologic features. To elucidate these conditions, Japanese validation study of CBD (J‐VAC study) group was established. The pathologic diagnosis is based on Office of Rare Diseases Neuropathologic Criteria for CBD proposed by Dickon et al. However, the identification of astrocytic inclusions sometimes revealed discordance among neuropathologists.

Methods: The aim is to standardize the pathologic diagnosis and elucidate the pitfalls of diagnostic process. The brains of Japanese 34 patients diagnosed pathologically as CBD from 12 institutes of J‐VAC study group were reviewed by an independently group of neuropathologists. They reviewed the slides blinded to clinical information, and filled out a datasheet.

Results: The age at onset was 64.9 (mean) years. Disease duration was 8.1 years. CBS/CBD was the most frequent final clinical diagnosis (46%), followed by PSP (28%) and DAT (10%).The astrocytic inclusions were observed in both the Gallyas silver staining method and tau immunostains. The pathologic review has been currently in process, and the diagnostic inconsistence was found between the institutes. The discordance of the pathologic diagnosis might depend on difficulties of observation of astrocytic inclusions and staining methods, especially on the Gallyas silver stain.

Conclusion: We report an interim progress. It is important to validate of the pathologic diagnosis of rare disease CBD.

P2‐25

Globular glial tauopathy(GGT) presenting corticobasal syndrome

Keizo Yasui¹; Nagako Maeda²; Maya Mimuro³; Yasushi Iwasaki³; Mari Yoshida³

¹Department of Neurology, Japanese Red Cross Nagoya Daini Hospital; ²Department of Pathology, Japanese Red Cross Nagoya Daini Hospital; ³Institute for Medical Science of Aging, Aichi Medical University

Introduction: GGT is a group of 4‐repeat tauopathies presenting with motor neuron disease and/or frontotemporal dementia.

Clinical summary: A 72‐year‐old Japanese woman developed body weight loss of 14kg, clumsiness of the left hand and unsteadiness of gait and then progressively worsened. Neurologically, she showed limb‐kinetic apraxia and pseudoathetosis of the left hand, and brisk tendon reflex on both sides with normal plantar reflex. Multiple lacunar infarcts were observed upon MR imaging. Dopamine transporter SPECT indicated decrease in the specific binding ratio bilaterally. She had a score on the Mini‐Mental State Examination of 29/30, Raven's Colored Progressive Matrices of 24/36, Frontal Assessment Battery of 11/18 and trail making test of set B of 180 seconds. Subsequently, parkinsonism, frozen gait, cognitive impairment, disinhibition, motor aphasia, and ocular apraxia became apparent. At the age of 77, her extremities changed into flaccid paralysis and nasogastric feeding tube was needed. Her disease duration was 5 years.

Pathological findings: Her brain weight was 1110g. Cerebral atrophy was observed predominantly on precentral gyrus, superior parietal lobule with subcortical white matter and corticospinal tract degeneration. Globus pallidus, subthalamic nucleus, and substantia nigra showed mild to moderate neuronal loss and gliosis. Numerous 4R immunoreactive globular oligodendroglial inclusions, threads, were found in these regions. Several 4R immunoreactive astrocytic inclusions were different from typical tufted astrocytes and astrocytic plaques. Senile change were NFT Braak/AT8 stage III/III with argyrophilic grain stage I. These pathological findings were compatible to GGT.

Conclusion: CBS may develop in some cases with GGT.

P2‐26

Neuropathologic characteristics of patients with progressive suprenuclear palsy who died within four years after the disease onset

Lu Zhang¹; Yasuko Toyoshima¹; Akari Takeshima¹; Hiroshi Shimizu¹; Itsuro Tomita³; Osamu Onodera²; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University, Niigata Japan; ²Department of Neurology, Brain Research Institute, Niigata University, Niigata Japan; ³Section of Neurology, Nagasaki Kita Hospital, Nagasaki, Japan

Introduction: Progressive supranuclear palsy (PSP) has been recognized as a tauopathy, and affected patients may manifest a wide variety of clinical symptoms. Practically, for patients with a short clinical course, a firm diagnosis of PSP may be difficult. Here we investigated the histopathological characteristics of autopsied patients with PSP who had died during the early stage.

Materials and Methods: From a total of 60 autopsy‐proven patients with PSP, we retrieved four in whom PSP had been suspected clinically, but who had died unexpectedly within 4 years after onset. Multiple paraffin‐embedded tissue sections throughout the brain were used for tau‐immunohistochemistry with the AT8 antibody and the Gallyas‐Braak silver method. Semi‐quantitative evaluation was performed.

Results: The degeneration pattern appeared to be similar in all patients, with moderate neuronal loss in the substantia nigra, mild loss in the globus pallidus and subthalamus, and mild gliosis in the cerebellar dentate nucleus. Interestingly, the tau distribution pattern was distinct from neuronal degeneration, and the degree of tau accumulation differed among patients; the basal ganglia and subthalamus were the most prominent sites, and the cerebral cortex, cerebellar dentate nucleus and brainstem were also involved. In the motor cortex and basal ganglia, tau had accumulated mainly in glia, whereas in the brainstem it was deposited in neurons.

Conclusion: The initial symptoms of PSP may be associated with neuronal degeneration. Vulnerability of neurons and glia to tau deposition appears to differ among brain regions and individual patients, suggesting an association with symptomatic variability.

P2‐27

Clinicopathological characteristics of progressive supranuclear palsy manifesting cerebral cortical symptoms

Akari Takeshima^1,2; Hiroshi Shimizu¹; Hidetomo Tanaka¹; Yasuhiro Aso³; Etsuro Matsubara³; Ko Tanaka⁴; Takashi Nakajima⁵; Hitoshi Takahashi¹; Osamu Onodera²; Akiyoshi Kakita¹

¹Pathology, Brain Research Institute, Niigata University, Niigata; ²Neurology, Brain Research Institute, Niigata University, Niigata; ³Neurology, Faculty of Medicine, Oita University, Oita; ⁴Psychiatry, Mishima Hospital, Niigata; ⁵Neurology, Niigata National Hospital, National Hospital Organization, Niigata

Introduction: There exists a wide clinical spectrum of progressive supranuclear palsy (PSP). The aim of the present study was to clarify the clinicopathological characteristics of Japanese patients with atypical PSP who exhibited cerebral cortical symptoms as an early and predominant feature.

Methods: We retrospectively reviewed the medical records of 59 patients with autopsy‐proven PSP. By using core features employed in the latest diagnostic criteria (Mov Disord 2017), we selected patients that showed cerebral cortical dysfunction (C1‐3) earlier than or within one year following the development of supranuclear gaze palsy (O1) and repeated falls (P1) (PSP‐CC group). We also selected patients with usual PSP that manifested O1 and P1 without or preceding C1‐3 features (PSP‐RS group). We quantified tau load in various brain regions including cerebral cortical, subcortical, and brainstem areas, paying attention to the lesion laterality.

Results: Six and seven cases comprised PSP‐CC and PSP‐RS groups, respectively. In the PSP‐CC group, a variety of cerebral cortical dysfunction, including speech disorder, bradyphrenia, disinhibition, and sensory deficit were observed. Tau load in the motor cortex and superior parietal lobule was significantly heavier in the PSP‐CC group. In addition, 3 from PSP‐CC group had a more severe cortical tau burden in the hemisphere ipsilateral to the side with predominant atrophy on brain MRI and decreased blood flow on SPECT.

Conclusions: Some patients with PSP manifest a variety of cerebral cortical dysfunction from early disease stage, likely as a result of severe and often asymmetrical cerebral cortical involvement.

P2‐28

An autopsied case of atypical tauopathy with globular glial inclusions

A Funai¹; K Masui^3,4; E Hoshino¹; H Kimura¹; R Okiyama¹; Y Nakata²; E Isozaki¹; T Komori³

¹Department of Neurology, Tokyo Metropolitan Neurological Hospital; ²Department of Neuroradiology, Tokyo Metropolitan Neurological Hospital; ³Pathology and Laboratory Medicine, Tokyo Metropolitan Neurological Hospital; ⁴Department of Pathology, Tokyo Women's Medical University

Introduction: Globular glial tauopathy (GGT) is a group of tauopathies characterized by widespread globular glial inclusions (GGIs). GGT, however, exhibits a wide range of clinicopathological features, making its definition ambiguous. We describe an autopsied case of atypical tauopathy with unique clinical presentation and distribution pattern of GGIs.

Clinical Summary: A 62‐year‐old woman presented with tremor and dyscoordination in her left limbs. She initially responded to L‐DOPA treatment, but further developed gait and cognitive disturbances. Her aunt displayed the similar symptoms. The imaging studies showed atrophy of the midbrain tegmentum and she was diagnosed to have progressive supranuclear palsy. Eventually, she became bedridden and died of aspiration pneumonia at the age of 79 after 17 years from her initial symptom.

Pathological findings: Postmortem examination revealed severe neurodegeneration with many phosphorylated‐tau‐positive neuronal as well as glial inclusions in the internal segment of the globus pallidum and subthalamic nuclei. The glial ones included globular oligodendroglial inclusions, coiled bodies and globular astrocytic inclusions. The latter rarely showed argyrophilic reactivity with Gallyas staining. These tau‐positive inclusions were also scattered in the frontal lobe, tegmentum of the brainstem, substantia nigra, inferior olive and dentate nuclei of the cerebellum.

Conclusions: Although the findings suggest the diagnosis of “GGT, type 2”, the clinical presentation, positive family history and distribution pattern of tau inclusions are not concordant with those of the type 2 reported. Further biochemical characterization of GGIs and molecular genetic analyses are to be necessary to establish more stringent criteria for GGT.

P2‐29

Pathologically suspected frontotemporal dementia and parkinsonism linked to chromosome 17: a case report in Japan

Shun Akaike¹; Kentaro Tokumoto^1,2; Ryoko Takeuchi¹; Hidehiro Shibayama¹; Toshio Fukutake¹; Shigeo Murayama²

¹Department of Neurology, Kameda Medical Center, Chiba, Japan; ²Department of Neuropathology and Neurology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology Department of Neurology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology

Introduction: Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17) is a major neurodegenerative syndrome characterised by behavioural and personality changes, cognitive decline, and motor symptoms. Case reports are limited on a sporadic case of the disorder.

Clinical summary: A 68‐year‐old Japanese man visited our hospital because of clumsiness of the left hand. No tremor was noted, but rigidity and bradykinesia were observed in the left hand. There was no family history of neurodegenerative disorder. Idiopathic Parkinson's disease was initially diagnosed. Later, the motor symptom was slightly advanced and cognitive decline developed although behavioural and personality abnormalities were not observed. At age of 88 years, he was admitted to our hospital because of multiple cerebral infarct. After several episodes of pneumonia due to dysphagia, he died.

Pathological findings: The substantia nigra was affected with predominantly left‐sided neuronal loss and gliosis. Both 3‐ and 4‐repeat taus were positive in neurons and astrocytes. Despite the presence of throne‐shaped astrocytes, astrocyte tangles were almost absent. Staining with anti‐amyloid beta peptides antibody showed classic and diffuse plaques only in the occipital lobe. Lewy bodies were observed in the left dorsal nucleus of vagus nerve, not in the substantia nigra or the locus ceruleus.

Conclusion: Clinical and pathological findings are suggestive of a diagnosis of FTDP‐17. Unfortunately, a definite diagnosis was not achieved because of insufficient sample volume available. Our case shows that FTDP‐17 should be considered in patients with atypical parkinsonism and cognitive decline despite absence of personality changes and family history.

P2‐30

An autopsy case of incipient Pick's disease with long‐standing history of schizophrenia

Keitaro Okada^1,2; Yukiko Hata²; Koji Yoshida^3,4; Tsutomu Takahashi⁵; Yoichiro Takayanagi⁵; Naoki Nishida²

¹University of Toyama, Toyama, Japan; ²Legal Medicine, Graduated School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; ³Neuroloby, Hyogo Brain and Heart Center, Hyogo, Japan; ⁴Neurology, Toyama University Hospital, Toyama, Japan; ⁵Neuropsychiatry, Graduated School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

Introduction: Neuropathology in the early stage of Pick disease remains poorly understood.

Clinical summary: The present report describes a 74‐year‐old female autopsy case of sudden arrhythmogenic death. Although she had a 37‐year history of schizophrenia and had been medicated, she was not limited in activities of daily life.

Pathological findings: Brain weight was 1,116 g. The only mild cerebral atrophy with dilatation of cerebral ventricle was found. Phosphorelated tau (AT8) and 3‐repeat‐tau positive Pick bodies (PBs) was found in the brain: These were relative frequent in inferior frontal, middle and inferior temporal, frontoorbital, ambient and cingulate gyrus, and was rarely in other gyrus of frontal and temporal lobe, limbic area. PBs in the neocortical region were more frequently found in ventral side and the upper (layer II) and lower (layer V and VI) layers. Moderate to large amount of AT8 positive neurofibrillary tangle and small amount of neuronal thread were found in limbic area and mid brain. Senile plaque and Lewy pathology was not found.

Conclusion: Although we determined that Pick disease in present case was incipient and did not have correlation with Schizophrenia in alive, PBs and other tau pathology may synergistically contribute to getting lost the way her home. The lack of distinct sign indicating frontotemporal dementia could be associated with restricted extension of neocortical PBs and lack of neuronal loss. Neuropathological examination for forensic autopsy cases could provide a better understanding of the pathological appearance of preclinical Pick's disease.

P2‐31

Immunohistochemical detection of phosphorylated alpha‐synuclein in the brain of a tauopathy model, rTg4510 mice

Yuta Takaichi¹; Yasuhisa Ano²; James Ken Chambers¹; Kazuyuki Uchida¹; Akihiko Takashima³; Hiroyuki Nakayama¹

¹Laboratory of Veterinary Pathology, The University of Tokyo; ²Research Laboratories for Health Science & Food Technologies and the Central Laboratories for Key Technologies, Kirin Company Ltd.; ³Department of Life Science, Gakushuin University

Introduction: The accumulation of specific phosphorylated protein aggregates in the brain is a hallmark of neurodegenerative disorders. Specifically, hyperphosphorylated tau (hp‐tau) accumulates in Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17, and progressive supranuclear palsy; furthermore, phosphorylated alpha‐synuclein (p‐aSyn) accumulates in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Moreover, co‐deposition of different pathological protein aggregates is common in the brains of individuals with neurodegenerative diseases.

Methods: We used rTg4510 mice that overexpress human P301L mutant tau, and FVB/N‐C57BL/6J mice. The mice were euthanized at 3, 6, 8.5, and 10 months of age, and the brains were collected. We searched hp‐tau and p‐aSyn deposition in the brain of the mice by immunohistochemistry.

Results: Human hp‐tau and mouse p‐aSyn aggregates were detected within the same neuronal cells mainly in the hippocampal CA1 area, entorhinal cortex and amygdala of rTg4510 mice and increased with age. Semi‐quantitative analysis revealed a significant regional correlation between hp‐tau and p‐aSyn accumulation.

Conclusion: The results indicate that endogenous mouse aSyn protein is phosphorylated and accumulates with hp‐tau aggregation in neurons, and suggest that the overexpression of human P301L mutant tau may enhance endogenous aSyn phosphorylation and aggregation via a similar hyperphosphorylation mechanism in vivo. This synergic effect between tau and aSyn accumulation may exacerbate the pathology of several neurodegenerative disorders with co‐occurrence of hp‐tau and p‐aSyn aggregation.

P2‐32

NODDING SYNDROME IN UGANDA: Histologic evidence for a novel frontotemporal degeneration tauopathy

Michael S. Pollanen^1,2; Sylvester Onzivua³

¹Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada; ²Ontario Forensic Pathology Service, Toronto, Ontario, Canada; ³Department of Pathology, College of Health Sciences, Makerere University, Kampala, Uganda

Nodding syndrome is an endemic neurologic disorder of unknown cause that affects children in the subsistence‐farming communities of East Africa. We report the neuropathologic findings in 5 fatal cases (13‐18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau‐immunoreactive neuronal neurofibrillary tangles, pre‐tangles, neuropil threads, and dot‐like lesions involving the cerebral cortex, subcortical nuclei and brainstem. Occasional tufted astrocytes and plaque‐like structures were also present. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving superficial cortical lamina. In severely involved areas of neocortex, there were tau‐immunoreactive threads in subcortical white matter. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. The pathologic features of nodding syndrome shared characteristics with both corticobasal degeneration and progressive supranuclear palsy. We conclude that nodding syndrome is a newly recognized neurodegenerative disease in East Africa and may represent a novel variant of frontotemporal degeneration tauopathy.

P2‐33

Phosphorylated tau deposition in the spinal motor neurons in sporadic amyotrophic lateral sclerosis

Takahiro Takeda; Ayako Kojima; Mizuho Koide; Nobuyuki Araki; Sagiri Isose; Kimiko Itoh; Kazuhiro Honda; Yasumasa Yoshiyama; Kimihito Arai

Department of Neurology, Chiba East Hospital

Less is known about tau accumulation in patients with amyotrophic lateral sclerosis (ALS). We investigated whether abnormal phosphorylated tau can accumulate in the spinal motor neurons in patients with ALS, and if any, which accumulation is predominantly composed of 3‐repeat or 4‐repeat phosphorylated tau. Eleven patients with ALS (7 men and 4 women)(mean age at death: 68.4 years) were enrolled in this study. With paraffin‐embedded axial slice of the spinal cord at the level of cervical, thoracic, lumbar and sacral segments, immunohistochemistry was performed. All the patients had TDP‐43‐positive cytoplasmic inclusions in the spinal motor neurons. Although, the distribution of AT‐8‐positive lesions was very sparse, the tau‐positive inclusions and neurites were detected in eight out of 11 patients with ALS. The cervical cord was the most frequently affected segment (five out of 11 patients (45.5%)), followed by thoracic (three patients (27.3%)) and lumbar (one patient (9.1%)). Tau pathology was not detected in the sacral segment. According to previous report, this prevalence of tau burden was almost equivalent to or less than that of normal aging spinal cord. The AT‐8 lesions were positive for 3‐repeat tau but negative for 4‐repeat tau. Because the number of patients was very small in this study, the relationship between tau lesions, TDP‐43 pathology and motor neuron sign could not be uncovered. Further study is needed to clarify whether TDP‐43 pathology could have a potential to contribute to the presence of tau pathology, and whether tau pathology could increase the clinical severity of ALS.

P2‐34

Are Bunina bodies generated as a byproduct in the process of TDP‐43 degradation?

F Mori¹; Y Miki¹; Y Seino²; K Tanji¹; T Yoshizawa³; H Kijima³; M Shoji²; K Wakabayashi¹

¹Department of Neuropathology, Hirosaki University Graduate School of Medicine; ²Department of Neurology, Hirosaki University Graduate School of Medicine; ³Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine

Introduction: Sporadic amyotrophic lateral sclerosis (sALS) is characterized pathologically by loss of motor neurons with occurrence of TDP‐43‐immunoreactive skein‐like and round inclusions. Lewy body‐like hyaline inclusions (LBHIs) are also found in a small proportion of sALS cases as well as in individuals with familial ALS with mutations of the Cu/Zu superoxide dismutase (SOD1) gene. LBHIs in sALS are immunopositive for TDP‐43, but not for SOD1. The occurrence of Bunina bodies (BBs) is another pathological feature of sALS. BBs are immunonegative for TDP‐43 but immunopositive for cystatin C, transferrin, peripherin and sortilin‐related receptor CNS expressed 2 (SorCS2). Despite differences between BBs and TDP‐43 inclusions in terms of protein constituents and ultrastructure, the two inclusions are known to be linked.

Subject: We investigated a case of sALS of 10 months’ duration in which many round inclusions, LBHIs and BBs were found in the anterior horn cells.

Results: Our immunohistochemical and ultrastructural studies revealed the presence of BBs within the skein‐like and round inclusions, and in the LBHIs. Co‐localization of BB‐related proteins (cystatin C, transferrin and SorCS2) and TDP‐43 was also confirmed in the halo of LBHIs as well as in the marginal portion of the skein‐like and round inclusions.

Conclusion: These findings support the possibility that BBs may originate from TDP‐43 inclusions. Considering that BB‐related proteins are involved in the lysosomal and endosomal pathway, BBs might be generated as a byproduct in the process of TDP‐43 degradation.

P2‐35

TDP‐43 pathology in FTLD‐subtypes

Yasushi Nishihira¹; Qinwen Mao¹; Missia Kohler¹; Giovanni Coppola⁶; Rosa Rademakers⁷; Alfred Rademaker³; Sandra Weintraub⁴; M‐Marsel Mesula^2,5; Changiz Geula⁵; Eileen H Bigio^1,5

¹Department of Pathology, Northwestern University Feinberg School of Medicine; ²Department of Neurology, Northwestern University Feinberg School of Medicine; ³Department of Preventative Medicine, Northwestern University Feinberg School of Medicine; ⁴Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine; ⁵Northwestern CNADC, Northwestern University Feinberg School of Medicine; ⁶Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles; ⁷Department of Neuroscience, Mayo Clinic, Jacksonville

Introduction: Following the discovery of 43‐kDa TAR DNA‐binding protein (TDP‐43) as the ubiquitinated protein in most cases of FTLD‐U, the harmonized classification of FTLD‐TDP was agreed upon, which includes four subtypes, FTLD‐TDP types A, B, C and D. Occasionally it is difficult to assign a case of FTLD‐TDP to a specific pathologic subtype.

Method: We formally re‐evaluated the TDP‐43‐ir pathologic features that characterize the different FTLD‐TDP subtypes to see if the current classification could be refined.

Result: In our series of 91 cases, 95% were classified as one of the common FTLD‐TDP subtype (35% A, 55% B, 10% C). The rest, 5%, did not easily fit into one specific FTLD‐TDP sub‐type. One case showed changes that were consistent with combined type B and type C pathology, one showed type B with NIIs, two showed type B or variant with some long, thin DNs, and one showed type C variant with NIIs. Of the 91 FTLD‐TDP cases, 20 had C9orf72 repeat expansions, which included 5 type A cases, 13 type B cases, the one combined type B and C case, and the one type B variant with NIIs case.

Conclusion: These findings suggest that the pathologic criteria for subtyping FTLD cases based on TDP‐43 immunohistochemistry (IHC) is useful. But up to 5% of FTLD‐TDP cases may have combined or unclassifiable TDP pathology that does not appear to be consistently associated with C9 repeat expansion, and in our cohort, only a minority of cases with C9 repeat expansion have combined FTLD‐TDP subtypes.

P2‐36

Immunohistochemical comparison of past and present patients with Kii amyotrophic lateral sclerosis

Kazumi Tsuji¹; Yoshiaki Nakayama¹; Takashi Ayaki²; Masaya Hironishi¹; Hidefumi Ito¹

¹Department of Neurology, Wakayama Medical University; ²Department of Neurology, Kyoto University Graduate School of Medicine

Introduction: Kii amyotrophic lateral sclerosis (ALS) is characterized neuropathologically by widespread tau pathology including neurofibrillary tangles (NFT) and various glial inclusions, in addition to the classical ALS pathology. In recent years, the incidence of ALS has decreased in south Wakayama Prefecture, but it is not clear that environmental change is the cause. In this study, we investigated whether changes in the environment may have affected the pathological features of Kii ALS.

Methods: We examined brain tissue from 6 Kii ALS patients autopsied between 1965 and 1977, and from 3 Kii ALS patients who died between 2013 and 2016, respectively.

Results: All 9 patients showed similar topography of NFT distribution in the motor cortex, frontal lobe, temporal lobe, hippocampus, amygdala, and brainstem. NFTs were observed predominantly in the superficial layer of these cerebral cortices. In addition, in all patients, we detected granular hazy inclusions and granular or fuzzy tau immunoreactivity in processes of astrocytes as glial cytoplasmic inclusions. The distribution of TDP‐43‐positive neurocytoplasmic inclusions (NCI) was similar among the 9 patients, with immunoreactivity detected in the spinal cord and cerebral cortices. The cortical distribution patterns of TDP‐43 pathology matched that of Type B of the Mackenzie's classification. Deposits of amyloid beta were either sparse or absent in all patients.

Conclusion: Our results suggest that the fundamental pathologic features of Kii ALS have not changed in patients over a range of years, in spite of changes in the environment.

P2‐37

Linear polyubiquitination occurs following K48‐linked polyubiquitination in Alzheimer's disease

Yoshiaki Nakayama¹; Kazumi Tsuji¹; Takashi Ayaki²; Hidefumi Ito¹

¹Department of Neurology, Wakayama Medical University; ²Department of Neurology, Kyoto University Graduate School of Medicine

Introduction: In patients with Alzheimer's disease (AD), various ubiquitinated pathologic structures are observed in the brain. During the ubiquitination of target proteins, several linkage forms of polyubiquitin chains are generated. Of these, the linear polyubiquitin (LUb) chain is believed to regulate NF‐kB signaling. We examined the expression of LUb chains and compared it to the expression of K48‐linked polyubiquitin (K48Ub) chains in AD‐affected brains using immunohistochemical techniques.

Methods: Hippocampal and temporal lobe tissue from the postmortem brains of 6 neuropathologically‐diagnosed patients with AD were analyzed. Paraffin‐embedded hippocampal and temporal lobe sections were examined immunohistochemically using anti‐LUb, anti‐K48Ub, and anti‐ubiquitin antibodies.

Results: Pathological structures such as dystrophic neurites of senile plaques, neurofibrillary tangles (NFT), neuropil threads, and granulovacuolar degeneration showed anti‐LUb antibody immunoreactivity. Among these structures, neuropil threads were stained to a lesser extent by LUb than by K48Ub staining. The ratio of LUb‐positive NFT to K48Ub‐positive NFT was significantly lower in the temporal lobe (11%) than in the CA1 (47%) region.

Conclusion: Our results demonstrate that a subset of ubiquitin‐positive pathological structures that appear in the AD‐affected brain also show LUb immunoreactivity. In the region where NFT appear later, the accumulation of LUb is less than that of K48Ub. This suggests that linear polyubiquitination occurs following K48‐linked polyubiquitination in the AD‐affected brain. Moreover, the lower degree of LUb immunoreactivity in neuropil threads suggests that the occurrence of linear polyubiquitination depends on the size of the substrate.

P2‐38

Clinicopathologic features of two patients with sporadic amyotrophic lateral sclerosis who maintained communication ability for over 30 years

Junko Ito¹; Tetsuro Shimada³; Mari Tada¹; Hiroshi Shimizu¹; Masatoshi Wakabayashi⁴; Akio Yokoseki²; Osamu Onodera²; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neurology, Brain Research Institute, Niigata University; ³Undergraduate Course, Niigata University School of Medicine; ⁴Ojiya Sakura Hospital

Introduction: A small proportion of sporadic amyotrophic lateral sclerosis (SALS) patients are able to survive for a long period. We report the clinicopathologic features of two unrelated patients with SALS receiving tracheostomy and invasive ventilation (TIV) support who were able to maintain their communication ability for more than 30 years after disease onset.

Case histories: Patient 1 was a 41‐years‐old woman who developed progressive muscle weakness. She introduced TIV at the age of 47 years. Her disease progressed extremely slowly, and she remained able to communicate via eye and mandibular movements until the end of her life. She died of liver failure at the age of 78 years.

Patient 2 was a 38‐years‐old man who developed bilateral lower limb weakness and spasm in the left lower limb. TIV was introduced at the age of 42 years. He was able to communicate via mandibular movements until the end of his life. He died of pulmonary alveolar proteinosis at the age of 69 years.

Pathological findings: The histopathological features of the CNS in patients 1 and 2 were quite similar. Neuronal loss was confined to the motor neuron system, and apparently mild in degree. As both patients showed phosphorylated TDP‐43‐immunoreactive neuronal cytoplasmic inclusions (NCIs) and glial cytoplasmic inclusions (GCIs) in the CNS, but the number of these inclusions was extremely small.

Discussion: There may be a distinct subgroup of patients with SALS, who can survive and maintain communication ability for an unusually long period, accompanied by very mild TDP‐43 pathology.

P2‐39

A Japanese autopsy case of sporadic frontotemporal lobar degeneration with TAR‐DNA binding protein 43‐positive inclusions (FTLD‐TDP) clinically diagnosed as corticobasal syndrome (CBS)

Yufuko Saito¹; Yoshihiko Horimoto²; Keizo Yasui³; Ikuko Aiba¹; Yasushi Iwasaki⁴; Maya Mimuro⁴; Mari Yoshida⁴

¹Department of Neurology, National Hospital Organization Higashinagoya National Hospital; ²Department of Neurology, Nagoya City Rihabiritation Center; ³Department of neurology, Japanese Red Cross Nagoya Daini Hospital; ⁴Institute for Medical Science of Aging, Aichi Medical University

Introduction: In many cases of FTLD‐TDP, frontotemporal dementia or semantic dementia symptoms precede asymmetric motor disturbances. We present a sporadic autopsy case of FTLD‐TDP in which motor disturbances preceded dementia symptoms, with a diagnosis of CBS.

Clinical summary: The patient was a man aged 33 years at onset, and the duration was 15 years. He presented with dysarthria, spastic gait disturbance, rigidity, and hyperreflexia on the right dominant side. At 11 years after onset, he showed behavioral‐variant frontotemporal dementia symptoms, such as hyperphagia, oral tendency, pica, and perseveration. Head magnetic resonance imaging revealed left hemi‐brain severe atrophy. Dopamine transporter single‐photon emission computed tomography with ioflupane showed specific binding ratio (SBR) decline on the left side. Thus, he was diagnosed with CBS.

Pathological findings: His brain weighed 840 g. Neuron loss with gliosis was seen from the frontal lobe and precentral gyrus to the parietooccipital lobes and at the anterior horn cells of the cervical spinal cord. The substantia nigra showed extremely severe neuron loss. Pyramidal tract degeneration was dominant on the left side, with severe small fiber loss. Immunostaining for phosphorylated TDP‐43 revealed short dystrophic neurites (DNs) and neuronal cytoplasmic and intranuclear inclusions in the cortex and basal ganglia. Although there were no Bunina bodies, skein‐like inclusions, or round inclusions, a few DNs and glial cytoplasmic inclusions were seen in the lower motor neurons.

Conclusion: The patient was pathologically diagnosed with FTLD‐TDP. It is difficult to diagnose FTLD‐TDP when asymmetrical motor impairments precede dementia.

P2‐40

An autopsy case of an elderly individual with incidentally diagnosed TDP‐43 proteinopathy

Yukiko Hata¹; Koji Yoshida^2,3; Naoki Nishida¹

¹Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; ²Department of Neurology, Hyogo brain and heart center, Hyogo, Japan; ³Department of Neurology, Toyama University Hospital, Toyama, Japan

Introduction: Neuropathology in the early stage of frontotemporal lobar degeneration with TDP‐43 proteinopathy remains poorly understood.

Clinical summary: The present report describes a 77‐year‐old male autopsy case of sudden cardiac death due to senile cardiac amyloidosis. Although he had a 15‐year history of hypertension and a 5‐year history of atrial fibrillation, he did not exhibit clinical history suggesting neuropsychiatric disease.

Pathological findings: Brain weight was 1,250 g. The atrophy was more severe in the anterior and basal side of the temporal pole. Restricted, but severe neuronal loss with neuronal cytoplasmic inclusions (NCIs) and dominant accumulation of TDP‐43 in the temporal pole, as well as in the entorhinal cortex and amygdala. Neuronal loss in the orbitofrontal cortex was not evident with little accumulation of TDP‐43. NCIs in the neocortical region were found in the upper layers (layer II and III) and lower layers (layer V and VI). A small number of dystrophic neurites (DNs) was also found in each area with an accumulation of TDP‐43. TDP‐43 accumulation was not found in the brain stem or spinal cord.

Conclusion: We determined that TDP‐43 pathology in the present case was not due to normal aging but may be significant pathological lesion. The lack of distinct clinical symptoms in the present case could be associated with restricted extension of neocortical TDP‐43 pathology and neuronal loss. We believe that neuropathological examination for forensic autopsy cases could provide a better understanding of the clinical and pathological appearance of preclinical or very early stage of TDP‐43 proteinopathy.

P2‐41

Distribution of phosphorylated TDP‐43 and phosphorylated tau in the temporal lobe of patients with sporadic ALS who died within one year after clinical onset

Kentaro Hayashi¹; Yoko Mochizuki²; Asa Nakahara³; Takashi Komori⁴; Akiyoshi Kakita³; Eiji Isozaki¹

¹Department of Neurology, Tokyo Metropolitan Neurological Hospital; ²Department of Neurology, Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled; ³Department of Pathology, Brain Research Institute, Niigata University; ⁴Department of Pathology, Tokyo Metropolitan Neurological Hospital

Introduction: We previously showed that amyotrophic lateral sclerosis (ALS) patients in the totally locked‐in state (communication stage V) showed rapidly‐progressing symptoms and common pathological lesions beyond motor neurons. Then we revealed that ALS patients who died within one year after onset showed phosphorylated TAR DNA‐binding protein 43 (pTDP‐43)‐immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) similar to those of stage V patients. Futhermore, we investigate the temporal lobe of the patients that contain NCIs in dentate granule neurons corresponding to Nishihira`s ALS type2.

Methods: We enrolled 6 patients who died within one year after clinical onset of sporadic ALS‐TDP‐43. We evaluated the degree of pTDP‐43‐ir and phosphorylated tau (AT8)‐ir NCIs semi‐quantitatively in the temporal tip, temporal cortex, hippocampal subiculum, and circular sulcus of insula.

Results: In the temporal tip, we found more pTDP‐43‐ir than AT8‐ir NCIs in 3 patients, fewer in 2 patients, and similar in 1 patients. In the hippocampal subiculum, AT8‐ir NCIs were observed along the perforant path, whereas pTDP‐43‐ir NCIs were observed outside of the perforant path. In the circular sulcus of insula, we observed pTDP‐43‐ir NCIs in all 6 patients and AT8‐ir NCIs in 5 patients, with the number of pTDP‐43‐ir NCIs exceeding that of AT8‐ir NCIs. The temporal cortex contained the least NCIs. Brrak NFT stage was I to III.

Conclusion: The temporal lobe of ALS‐TDP‐43 patients even within one year after onset contained pTDP‐43 and AT8‐ir NCIs in the same area as patients with ALS‐FTLD. The circular sulcus of insula was the affected area.

P2‐42

Morphological alterations of spinal motor neurons with dendritic and axonal TDP‐43 accumulation in patients with ALS type 2b

Asa Nakahara¹; Mari Tada¹; Tomoe Sato^1,2; Ryoko Takeuchi^1,3; Yasuko Kuroha⁴; Ryoko Koike⁴; Takashi Nakajima⁵; Osamu Onodera²; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neurology, Brain Research Institute, Niigata University; ³Department of Neurology, Kameda Medical Center; ⁴Department of Neurology, Nishi‐Niigata Chuo National Hospital; ⁵Department of Neurology, Niigata National Hospital

Introduction: ALS type 2b (ALS‐2b) is a distinct subgroup of ALS‐TDP characterized by accumulation of phosphorylated TDP‐43 in dendritic spines and axon terminals. The prognosis of patients with ALS‐2b is poor, despite relative preservation of lower motor neurons in comparison with other ALS‐TDP subgroups. This study aimed to clarify the morphological alterations of spinal motor neurons in ALS‐2b.

Methods: We examined the spinal L4 segment from 5 patients diagnosed pathologically as having ALS‐2b and 3 controls. We performed immunohistochemistry and double‐labeling immunofluorescence using antibodies against TDP‐43, choline acetyltransferase (ChAT), and trans‐Golgi network. ChAT‐positive neurons in the anterior horns were regarded as motor neurons, and the frequency of both Golgi apparatus (GA) fragmentation and nuclear clearance of TDP‐43 was evaluated.

Results: GA fragmentation and TDP‐43 nuclear clearance were significantly more frequent in ALS‐2b than in controls (GA: 91±8.4% and 13±13%, p<0.001, TDP‐43: 85±10% and 37±15%, p<0.001, respectively). Almost all motor neurons with TDP‐43 nuclear clearance showed GA fragmentation in ALS‐2b, but such neurons were rarely seen in controls. Interestingly, the motor neurons with TDP‐43 nuclear clearance in ALS‐2b harbored no TDP‐43‐positive cytoplasmic inclusions, and moreover abundant dendritic and axonal accumulation of TDP‐43 was evident.

Conclusion: In ALS‐2b, motor neurons show distinct morphological alterations probably associated with dendritic and axonal accumulation of TDP‐43, suggesting progressive dysfunction in the spinal motor neurons, and thus explaining the poor prognosis.

P2‐43

Autopsy‐proven amyotrophic lateral sclerosis coexisted with Parkinson's disease: a novel association of TDP‐43 proteinopathy and a‐synucleinopathy (ALS/PD in Tokushima)

Yuishin Izumi¹; Ryosuke Miyamoto¹; Koji Fujita¹; Hiroyuki Sumikura²; Yasuhiro Sakashita²; Hiroyuki Nodera¹; Toshitaka Kawarai¹; Yshihiko Nishida³; Shigeo Murayama²; Ryuji Kaji¹

¹Department of Neurology, Tokushima University Hospital; ²Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ³Department of Neurology, Itsuki Hospital

Introduction: Coexistence of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) with Lewy bodies (LB) is reported to be rare, except for ALS/PD Complex in Guam or Kii Peninsula (ALS/PDC Kii).

Methods: We screened 320 patients with ALS registered to the Tokushima University Hospital in Shikoku Island, Japan. We extracted ALS patients who showed parkinsonism during their clinical courses and evaluated their neurological and neuroimaging findings.

Results: The autopsy of three patients demonstrated ALS‐TDP‐43 complicated by PD with LB. On gross inspection, we observed depigmentation of the substantia nigra and locus ceruleus as well as atrophy of the spinal ventral roots in both patients. Microscopically, degeneration including neuronal loss with gliosis was observed in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, nucleus of the hypoglossal nerve, and ventral horn of the spinal cord. The involvement of upper motor neurons was confirmed by degeneration of the corticospinal tract and loss of Betz cells in the precentral gyrus. Bunina bodies were identified in lower motor neurons. Phosphorylated TDP‐43‐immunoreactive neuronal cytoplasmic skein or round inclusions and glial inclusions were observed in upper and lower motor neuron areas as well as in non‐motor areas in one case. Lewy bodies immunoreactive for phosphorylated a‐synuclein were abundant in the central and peripheral nervous systems. These cases lacked tau pathology and, thus, were distinct from ALS/PDC Kii.

Conclusions: Our investigation supports the possible establishment of a new disease entity and broadens the spectrum of proteinopathy in ALS and PD (ALS/PD in Tokushima).

P2‐44

An autopsy case of amyotrophic lateral sclerosis with a TARDBP N358S mutation

Naoyuki Kitagawa¹; Akiko Uchino²; Hirohumi Yamashita³; Makoto Urushitani³; Takashi Nonaka⁴; Masato Hasegawa⁴; Michio Sakurai^1,4; Shigeo Murayama²

¹Department of Neurology, Kohsei Chuo General Hospital; ²Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ³Department of Neurology, University of Kyoto; ⁴Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science

We report the first autopsy case of a thirty‐nine year old Japanese woman with a novel TARDBP N358S mutation, presenting with predominant upper motor signs. She experienced one‐ month history of dysarthria and gait difficulty. At her first visit to our clinic, she presented pseudobulbar type dysarthria and proximal dominant weakness accompanying hyperreflexia without muscle atrophy. Babinski sign was negative. Needle electoromyography detected resting potential in her limbs and trunks. Sequencing of the coding regions of the TARDBP disclosed a single base‐pair change at position 1073 from A‐to‐G (A1073G) in exon 6 (N358S mutation) in this patient and her father. No mutation in SOD1 nor FUS was found. She became bedridden due to progressive weakness one month later and died of respiratory failure 99 days after the admission. Neuropathologically, there were severe degeneration of primary motor area and mild affection of spinal anterior horn. Immunohistochemsitry with phosphorylated TDP43 demonstrated positive cytoplasmic round inclusions in the precentral cortex and anterior horn cells of the spinal cord. We studied the self‐association of the wild type (wt) and N358S mutation by utilizing Thioflavin‐S (ThS) binding assay. N358S mutation peptide showed significant fluorescence upon binding to ThS. Unlike the previously reported ALS cases with TARDBP mutation, our case presented prominent loss of upper motor neurons, commensurate with clinical signs. Further studies are needed to elucidate the pathological role of N358S mutation in TARDBP.

P2‐45

Amyotrophic lateral sclerosis‐associated Ataxin‐2 colocalized to ribosomal protein S6 in the human brain

Ryohei Watanabe¹; Shinji Higashi¹; Masayuki Ide¹; Kenichi Oshima²; Kazuhiro Niizato²; Tetsuaki Arai¹

¹Department of Psychiatry, University of Tsukuba; ²Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital

Introduction: There is a growing evidence indicating that Ataxin‐2 (ATXN2) is important as a modifier of amyotrophic lateral sclerosis (ALS) and its potential therapeutic target. To understand the physiological role of ATXN2 and its involvement in ALS, we have investigated the localization of ATXN2 protein in the human brain.

Methods: We examined two normal human brain subjects, of which one was 4% paraformaldehyde‐fixed, frozen floating sections, and the other was formalin‐fixed, paraffin‐embedded tissue sections. We performed a single immunoperoxidase labeling or a double immunofluorescence labeling using organelle specific antibodies, to analyze the anatomical or cellular distribution of ATXN2 protein. Colocalization of proteins were statistically analyzed according to the Pearson correlation coefficient and the Manders’ overlap coefficient methods.

Results: The sensitivity of anti‐ATXN2 immunoreactivity was higher in floating sections than in paraffin sections, indicating that anti‐ATXN2 sensitivity was influenced by fixation methods. ATXN2 protein is observed in distinct neurons of the cerebral cortex, hippocampus, striatum and midbrain, and localizes to the neuronal perikarya predominantly, and to their proximal dendritic and axonal processes to a lesser extent. Double immunofluorescence labeling experiments revealed that of ATXN2 positive neurons, 70% of them were S6‐positive and 50% were calnexin or LC3B positive.

Conclusion: The present study shows the highest rate of localization of ATXN2 in the ribosomes in neurons of the human brain. The results are consistent with the hypothesis that disruption of RNA metabolism involves in the pathogenesis of ALS.

P2‐46

What can neurophysiologists learn from neuropathology in diagnosis of amyotrophic lateral sclerosis (ALS)?

Mana Higashihara^1,2; Renpei Sengoku^2,3; Tomoyasu Matsubara³; Yasushi Nishina²; Kazutomi Kanemaru²; Masahiro Sonoo⁴; Steve Vucic⁵; Shigeo Murayama^2,3

¹Department of Neurology, Westmead Hospital; ²Department of Neurology, Tokyo Metropolitan Geriatric Hospital; ³Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital; ⁴Department of Neurology, Teikyo University School of Medicine; ⁵Westmead Clinical School, University of Sydney

Background: Clinical neurophysiological studies form a core in diagnosis of ALS. However, those cases without upper motor neuron (UMN) signs always cause problems.

Method: We conducted internationally standard neurophysiological protocol for diagnosis of ALS and recruited suspected patients for brain donation. Four patients donated their bodies between 2015 and 2017. Three of them fitted into clinically probable or definite ALS and one lacked UMN signs. Neurological examinations, electromyography (EMG) and pathological findings of the last case were comparatively reviewed.

Case reports: The patient was an 81 year‐old man with progressive weakness of the right upper and lower limbs. Needle EMG revealed denervation potentials and chronic neurogenic changes but the EMG abnormality did not meet diagnostic criteria. UMN signs and dementia were not evident throughout the course. He died three years later. Neuropathological examination revealed severe loss of spinal anterior horn cells with Bunina bodies and TDP proteinopathy (Brettschneider Stage 2). Extensive examination of the primary motor area (PMA) detected a very few neuronophagia of Betz cells in contrast with other three cases.

Discussion and Conclusion: Our series fulfilled pathological criteria of ALS but severity in the involvement of PMA was commensurate with clinical findings. The presented case did not have a chance for clinical trials and then more sensitive clinical method to detect involvement of UMN is required. In addition, this difference in severity of the involvement of UMN may represent different species of accumulated TDP‐43 just like prion disease. Further correlative clinical, physiological and pathological studies are indicated.

P2‐47

Upregulated expression of activated caspase‐9 immunoreactivity in brains with alpha‐synucleinopathy

Yasuhiro Kawamoto¹; Takashi Ayaki²; Fuminori Shimizu³; Ryosuke Takahashi²

¹Department of Neurology, Seijinkai Rakusaishimizu Hospital; ²Department of Neurology, Kyoto University; ³Department of Neurosurgery, Seijinkai Shimizu Hospital

Introduction: The mitochondria play an important role in apoptotic cell death, and the released cytochrome c from the mitochondria promotes the formation of the apoptosome, which contains cytochrome c, Apaf‐1 and caspase‐9, resulting in the activation of caspase‐9 and the promotion of the apoptotic cascade. The purpose of this study is to investigate the role of mitochondria‐related apoptosis in patients with alpha‐synucleinopathies.

Methods: Formalin‐fixed, paraffin‐embedded sections from 8 normal subjects, 10 patients with Parkinson disease (PD), 5 patients with dementia with Lewy bodies (DLB) and 10 patients with multiple system atrophy (MSA) were prepared. The deparaffinized sections were immunostained with primary antibodies against cytochrome c, Apaf‐1, caspase‐9 and activated caspase‐9. Some sections were double‐immunostained with activated caspase‐9 and alpha‐synuclein or glial markers.

Results: In the normal brains, various types of neurons were immunostained with cytochrome c, Apaf‐1 and caspase‐9, but no or faint activated caspase‐9 immunoreactivity was observed. In the diseased brains, activated caspase‐9 immunoreactivity was increased in both neuronal and glial elements, and 70‐80% of brainstem‐type and cortical Lewy bodies (LBs), glial cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) were intensely immunoreactive for activated caspase‐9. Brainstem‐type and cortical LBs, GCIs and NCIs were also immunopositive for cytochrome c, Apaf‐1 and caspase‐9.

Conclusion: Our results suggest that the formation of the apoptosome accompanied by the activation of caspase‐9 may occur in brains affected by PD, DLB and MSA, and that mitochondria‐related apoptosis may be associated with the pathogenesis of alpha‐synucleinopathies.

P2‐48

Four cases of multiple system atrophy with marked cortical atrophy and neuronal cytoplasmic inclusions in the temporal cortex

Takashi Ando^1,2; Maya Mimuro²; Yasushi Iwasaki²; Masahisa Katsuno¹; Mari Yoshida²

¹Department of Neurology, Nagoya University Graduate School of Medicine; ²Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease, which manifests as a combination of dysautonomia, cerebellar dysfunction, and parkinsonism. Generally, the neocortex and limbic systems show less pathological changes in MSA. However, atypical MSA with frontotemporal lobe degeneration have been reported. We report four autopsy cases with marked cortical atrophy and neuronal cytoplasmic inclusions (NCIs) in the temporal cortex.

Methods: We reviewed 159 consecutively autopsied Japanese patients with pathologically diagnosed MSA at our institute.

Results: Four patients (2.5%; one male and three females; age at onset, 45, 41, 60, and 63 years, respectively) were diagnosed with atypical MSA with prominent temporal lobe degeneration. All the patients were clinically diagnosed with MSA in the premortem period (one MSA‐C, three MSA‐P). Memory impairment was observed in three cases, but none had features of frontotemporal dementia. The disease duration was 25, 15, 14, and 14 years, respectively. Pathologically, all the cases met the criteria for MSA, which included severe olivopontocerebellar degeneration and various striatonigral degenerations with glial cytoplasmic inclusions. All the cases showed temporal atrophy with limbic alpha‐‐synuclein‐positive NCI and neurites. Varying degrees of NCI were observed in the frontal cortex, basal ganglia, and brainstem. One case showed the presence of Lewy bodies in the brain stem and sympathetic ganglion.

Conclusion: In our cohort, atypical MSA with temporal lobe degeneration was diagnosed antemortem and had long disease duration. Pathologically, NCI distribution was prominent in limbic systems but was spread to the frontal cortex, basal ganglia, and brainstem to a varying degree.

P2‐49

Dynactin is involved in Lewy body pathology

Hiroyuki Honda¹; Chang Shen¹; Satoshi O Suzuki¹; Naokazu Sasagasako²; Toru Iwaki¹

¹Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University; ²Department of Neurology, Neuro‐Muscular Center, National Omuta Hospital, Fukuoka, Japan

Introduction: Dynactin forms a protein complex with dynein and the complex transports cargo retrogradely along microtubules. Dysfunction of the dynein‐dynactin complex causes several neurodegenerative disorders, such as Perry syndrome. Recently, we reported colocalization of phosphorylated alpha‐synuclein (p‐SCNA) and the largest subunit of dynactin (DCTN1) in Lewy body‐like structures in Perry syndrome. However, the relationship between dynactin and synucleinopathies has not been clarified. In this study, we examined the possible involvement of the dynein‐dynactin complex in synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Methods

We examined 13 autopsied human brains of patients with synucleinopathy (5 PD, 5 DLB and 3 MSA). Immunohistochemistry for p‐SNCA, DCTN1 (dynactin) and DYNC1I1 (dynein) was performed. We also examined microtubule affinity regulating kinases (p‐MARKs), which phosphorylate microtubule‐associated proteins and trigger microtubule disruption. Double immunofluorescence was also performed. Results

Both brainstem and cortical Lewy bodies were immunopositive for DCTN1, DYNC1I1 and p‐MARK and their stainings often overlapped with p‐SNCA. Lewy neurites were also immunopositive for DCTN1 and DYNC1I1. However, p‐SNCA‐positive inclusions of MSA such as glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were negative for DCTN1, DYNC1I1 and p‐MARK.

Conclusion: Our results suggest that dynactin is closely associated with Lewy body pathology. In addition, immunohistochemistry for dynein‐dynactin complex molecules, especially DCTN1, can distinguish Lewy bodies clearly from neuronal cytoplasmic inclusions of MSA.

P2‐50

The Lewy body pathology of pedunculopontine nucleus in Lewy body disease with postural abnormality

Terunori Sano¹; Kanako Komatsu¹; Yohei Mukai²; Yuji Saitoh²; Tadashi Tsukamoto²; Takashi Sakamoto²; Yuji Takahashi²; Miho Murata²; Yuko Saito¹

¹Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry; ²Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry

Introduction: Pedunculopontine nucleus (PPN) is considered as responsible lesion for postural abnormality of Lewy body disease (LBD). Our aim is to evaluate the severity of Lewy body pathology of PPN in autopsy cases of LBD between with and without postural abnormality.

Methods: From the autopsy cases registered at our hospital, we used 17 consecutive autopsy cases that had been pathologically diagnosed with LBD. The location of PPN is identified by anti‐CHAT antibody staining at 2 sections between red nucleus and locus ceruleus in brainstem. Phosphorylated alpha‐synuclein staining was performed and the Lewy body pathology grading was evaluated according to the 4th DLB consensus guideline.

Results: The mean age at death was 76.8 ± 9.3 (mean ± SD) and the mean age at onset of LBD was 63.3 ± 11.0. Five cases clinically showed postural abnormality, camptocormia and/ or dropped head. About the Lewy body type pathology, 10 cases were neocortical type, 6 cases were limbic type and 1 case was brainstem type. The mean grade of Lewy body pathology in PPN of cases with postural abnormality was higher than that without postural abnormality. There was a tendency of more severe Lewy body pathology in the cases with postural abnormality, although there is no significant statistical difference.

Conclusion: LBD patients with postural abnormalities tended to have more severe Lewy body pathology in PPN. There is a possibility that Lewy body pathology of PPN is related with postural abnormality of LBD.

P2‐51

An autopsy case of Parkinson's disease with RecNciI (L444P‐ A456P‐ V460) glucocerebrosidase gene (GBA) mutation

Kimiko Inoue¹; Yuko Mori²; Keiko Toyooka¹; Misaki Yamadera¹; Chiaki Mori¹; Rika Yamashita¹; Yuki Yonenobu¹; Tomoko Oeda²; Harutoshi Fujimura¹

¹Department of Neurology, Toneyama National Hospital; ²Clinical Research Center and Department of Neurology, Utano National Hospital

Introduction: Mutations of β‐ glucocerebrosidase gene (GBA) are known as a risk factor for Parkinson's disease (PD). It was reported that clinical features of PD with GBA mutation (GBA‐ PD) were rapid progression of motor symptoms and severe non‐motor symptoms in their clinical course, while pathology of GBA‐ PD was not different from PD without GBA mutation. We describe a first autopsy report of GBA‐ PD with RecNciI (L444P‐ A456P‐ V460) GBA mutation.

Clinical Summary: A 68‐ year‐ old man noticed gait disturbance and frozen gait. REM sleep behavior disorder and hallucination occurred after one year of the onset. On hospital admission at the age of 70, the neurological examination disclosed Parkinsonism, autonomic failure, hallucination and dementia. UPDRS‐ III score and MMSE revealed 16 and 19 points respectively. The DNA analysis of the GBA gene revealed RecNciI (L444P‐ A456P‐ V460) mutations. His symptoms deteriorated rapidly, and died of pneumonia at the age of 73.

Pathological findings: The brain weight was 1056g pre‐ fixed. Loss of pigmentation from substantia nigra and locus ceruleus were found, and microscopic examination revealed that neuronal loss with reactive astrocytosis in these structures, as well as dorsal nucleus of vagus, nucleus basalis of Meynert and amygdala. Numerous Lewy bodies were found as ‘diffuse neocortical type’ of third DLB consortium criteria. The severity of concurrent NFT was mild (Braak sate I), and no amyloid plaque was found.

Conclusion: In this case, cardinal hallmark of dementia was considered as the pure acceleration of alpha‐ synuclein, and independent from Alzheimer pathology.

P2‐52

Submandibular gland is useful for diagnosis of Lewy body disease‐ the first report from Japan

Yasuhiro Sakashita^1,2,3,4; Renpei Sengoku¹; Yuko Saito³; Tomio Arai²; Masahito Yamada⁴; Shigeo Murayama¹

¹Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan; ²Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Gerontology, Tokyo, Japan; ³Department of Pathology and Laboratory Medicine, National Center of Neurology and Psychiatry Hospital, Tokyo, Japan; ⁴Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan

Introduction: Pathological diagnosis of Lewy body (LB) disease (LBD) is based on the presence of LB‐type α‐synucleinopathy (LBAS) at autopsy. We already reported that skin biopsy is useful to detect LBAS. In this study, we tried to calculate sensitivity and specificity of LBAS in submandibular gland (SG) in Japanese, to support the study now conducted in US.

Methods: We retrospectively examined LBAS of SG in 175 consecutive autopsy cases, who had intracytoplasmic LBAS in the central nervous system and evaluated sensitivity. Next, we prospectively examined LBAS of SG in 34 consecutive autopsy cases to check specificity.

Results: The employed 174 cases were classified into 60 cases of the Brain Bank for Aging Research (BBAR) LB Stage II, 16 cases of Stage III, 55 cases of Stage IV, and 43 cases of Stage V. LBAS was detected in 38 (63.3%) of Stage II, 13 (81.3%) of Stage III, 41 (74.5%) of Stage IV, and 35 (81.4%) of Stage V. Thus, the sensitivity was 73.0%. The prospectively studied cases included 23 cases of BBAR LB Stage 0, 4 cases of Stage 0.5, 1 case of Stage I, 1 case of Stage II, 1 case of Stage II, 3 cases of Stage IV and one case of Stage V. Among these, LBAS was found in all the cases of Stage II to V and no LBAS was found in Stage 0 to I. Thus, the specificity was 100 %.

Conclusion: This study confirmed usefulness of SG biopsy for diagnosis of LBD in Japanese.

P2‐53

Clinicopathological characteristics of pure type Lewy body disease with dementia

Renpei Sengoku^1,2; Yasushi Nishina¹; Yuko Saito³; Kazutomi Kanemaru¹; Shigeo Murayama^1,2

¹Department of Neuropathology, Tokyo Metropolitan Geristric Hospital and BrainBank for Aging Research; ²Department of Neurology, Tokyo Metropolitan Geristric Hospital; ³Department of Pathology, National Center for Neurology and Psychiatry Hospital

Introduction: Very few studies referred to which component of dementia symptoms were associated with concomitant Alzheimer pathology in Parkinson's disease with dementia (PDD)/ dementia with Lewy bodies (DLB). This study aimed to clarify clinicopathological characteristics of pure type Lewy body (LB) disease with dementia (i.e. neuropathologically confirmed PDD or DLB cases without significant other neurodegenerative or vascular changes).

Methods: Consecutive 820 autopsy cases from 2002 to 2013 in our institute included 79 PDD/ DLB cases. We excluded cases with significant senile changes (Braak neurofibrillary tangle stage, equal to or more than 3, plaque stage B and Saito's argyrophilic grain stage 2). We also excluded cases accompanied by symptomatic cerebrovascular disease, metabolic encephalopathy and other neurodegenerative diseases including progressive supranuclear palsy and corticobasal degeneration.

Results: 10 cases were selected as pure PDD/ DLB. Male to female ratio was 6:4 and the average age at death was 82.9 years. The average brain weight was 1165g. Nine cases were classified into Braak LB stage 4 and the remaining one to Stage 5. Clinical diagnosis of five cases was PDD; two, DLB; two, Alzheimer disease (AD); and one, pure autonomic failure. Four cases died of pneumonia, four cases experienced unexpected sudden death, and another two cases died of cancer. Five cases had history of hallucinations and seven cases had truncal rigidity including neck.

Conclusions: Our study highlighted difficulty in differential diagnosis of Lewy body dementia with AD. Our study also pointed out sudden death as a major cause of death in this group.

P2‐54

α‐synuclein pathology in phrenic nerves of Lewy body disease. (In Japan)

Kanako Komatsu¹; Terunori Sano¹; Yuji Takahashi²; Miho Murata²; Shigeo Murayama³; Yuko Saito¹

¹Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry; ²Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry; ³Brain Bank for Aging Research, Department of Neuropathology, Department of Neurology Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: Although restrictive respiratory disorder in Parkinson's disease is a clinical problem, the cause is not yet clear. Now, we focus on α‐synuclein deposition in the phrenic nerve and compare it with systemic pathology. Methods α‐synuclein deposition in the phrenic nerve and diaphragmatic intramuscular nerve (i.e. a more distal extension of the phrenic nerve) was assessed in 15 autopsied cases of Lewy body disease, and compared with the progression of Lewy body pathology throughout the body.

Results: Average age of the 15 cases was 75.8 ± 8.8 years. Based on Brain bank for aging research (BBAR) staging criteria, 3 cases were stage 1, 2 were stage 3, 2 was stage 4, and 8 were stage 5. There was only 1 case that did not have α‐synuclein deposits in phrenic nerves nor diaphragmatic intramuscular nerves. This case was BBAR stage 1. Six cases were positive in both nerves. The staging results for these cases; 3 cases were BBAR stage 5, 2 were stage 2 and 1 was stage 1. Five cases were positive in the phrenic nerve only; 3 cases in stage5 and 2 cases in stage 3. In 3 cases, positive findings were found only in the intramuscular nerve; 2 cases were BBAR stage 5 and 1 was BBAR stage 1.

Conclusion: α‐synuclein deposition in the phrenic nerve of Lewy body disease can be observed from early stages on. The more advanced the systemic Lewy pathology, the more likely it is that positive findings are seen.

P2‐55

Acute swelling of medulla oblongata followed by sudden death in a case of MSA‐ C

Yuko Hiroyoshi; Kazutomi Kanemaru; Shigeo Murayama

Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology

Introduction: We report a unique pathological change observed in a 59‐year‐old man with MSA.

Clinical summary: His initial symptoms at age 50 were dysarthria and unsteady gait, followed by neurogenic bladder and dysphagia. Just prior to death, he was admitted to our hospital for aspiration pneumonia. Neurologically he presented with rigidity, cerebellar ataxia and myoclonus. MRI showed swelling in T1WI and high inensity in T2WI and FLAIR involving the medulla oblongata. Since his general condition was stable, he was discharged but visited the emergency ward ten days later. He died of acute respiratory failure.

Pathological findings: The brain weighted 1.315g. Macroscopically cerebellum and brain stem was atrophic but medulla oblongata apparently preserved its normal size. Typical changes of MSA with glial cytoplasmic inclusions were present in putamen, substantia nigra, base of pons, cerebellar cortex, inferior olivary nucleus and spinal cord. In addition, swelling with severe vacuolar changes and axonal spheroids accompanying agonal hemorrhage involved medulla oblongata.

Conclusion: This change may explain his unexpected death, but correlation with MSA may need further accumulation of similar cases.

P2‐56

Alpha‐synuclein pathologies associated with deep brain stimulation in Parkinson's disease

Masashi Takanashi¹; Genko Ohyama^1,2; Daisuke Taniguchi¹; Atsushi Umemura^2,3; Yasuji Shimo^1,2; Nobutaka Hattori¹

¹Department of Neurology Juntendo University School of Medicine; ²Department of Research and Therapeutics for Movement Disorders Juntendo University School of Medicine; ³Department of Neurosurgery Juntendo University School of Medicine

Introduction: Deep brain stimulation (DBS) is a surgical treatment for advanced and complicated Parkinson's disease (PD). Alpha‐synuclein (a‐syn) pathologies of PD with DBS has been reportedly various. We will present a‐syn pathologies of two cases of autopsied PD with DBS.

Clinical summary: Two patients were sporadic and typical PD with severe wearing off and dyskinesia. Bilateral DBS leads had been previously implanted in the subthalamic nucleus (STN) for both patients. DBS was very beneficial for motor complications and kept good conditions over ten years.

Pathological findings: The pathologies of two patients showed degeneration in the substantia nigra, locus ceruleus, and dorsal motor nucleus of vagus, and Lewy pathologies. Stagings of Lewy pathologies were limbic type and Braak stage 4. One patient showed a‐syn pathologies around the DBS electrode incision, and another showed oligodendroglial a‐syn pathologies along electrode of DBS.

Conclusion: We experienced a‐syn pathologies associated with DBS. Relationship between DBS and a‐syn pathologies is still controversial. Our two cases may bring important information about mechanism of a‐syn accumulation in patients with DBS.

P2‐57

Oxidative stress and uric acid are associated with pathomechanism of multiple system atrophy

Shigeru Koyano^1,2; Mikiko Tada²; Shunta Hashiguchi²; Hiroshi Doi²; Fumiaki Tanaka²

¹Department of Neurology, Yokohama Minami Kyousai Hospital; ²Department of Neurology, Yokohama City University

Introduction: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder and oxidative stress may partly contribute its pathogenesis. Uric acid protects neurons in neurodegenerative disorders via antioxidative effects. The aim of this study was to investigate the pathological relationship between uric acid and dityrosine, a marker for oxidatively modified proteins, in MSA.

Methods: In this study, using specific monoclonal antibodies against uric acid and oxidative stress marker, dityrosine, we performed an immunohistochemical analysis in sections of archival, formalin‐fixed, paraffin‐embedded brain materials of five MSA patients and two control subjects.

Results: Dityrosine immunoreactivity was prominently observed in neurons, glia and perivascular areas in the cerebellum, inferior olivary nucleus and basal ganglia including putamen, all of which are related to the pathological lesions of MSA. However, it was not detectable in all of the neuronal cytoplasmic inclusions and glial cytoplasmic inclusions. Overall, uric acid immunoreactivity was weak in whole regions of MSA brain. By contrast, dityrosine immunoreactivity in the control cases was very weak or undetectable in the parenchymal cells including neurons and glia and control brains were totally more stained by uric acid than MSA.

Conclusion: These pathological observations implicate the tyrosine oxidative stress in the pathomechanism of MSA.

P2‐58

Accumulation of prostease‐resistant alpha‐synuclein in the skin

Masako Ikemura¹; Yuko Saito²; Tomio Arai³; Masashi Fukayama¹; Shigeo Murayama⁴

¹Department of Pathology, Graduate School of Medicine, The University of Tokyo; ²Department of Laboratory Medicine, National Center for Neurology and Psychiatry; ³Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ⁴Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: We previously reported that phosphorylated α‐synuclein (psyn) positive (Lewy body) LB‐related pathology involved the cutaneous nerves in Lewy body disease (LBD). However, the sensitivity was insufficient to establish skin biopsy as a diagnostic tool for LBD. The aim of the present study was to analyze the accumulation of the protease‐resistant α‐synuclein in the skin.

Methods: Cutaneous LB pathology was evaluated in retrospective autopsy cases of LBD (148cases) and in biopsy specimens with clinically suspected LBD (7cases) by immunohistochemistry, using α‐synuclein antibody with pretreatment of Proteinase K (PK).

Results: The PK‐resistant α‐synuclein was deposited in nerve fascicles mainly around blood vessels in LBD, but not in control subjects. Immunoreactivity of PK‐resistant α‐synuclein was more intense and was observed more frequently than that of psyn. The rates of skin PK‐resistant syn positivity (%) at each CNS LB stage were as follows: 57.7% in incidental Parkinson 's disease (PD), 88.2% in PD and PD with dementia and 53.8% in dementia with Lewy bodies. In all CNS LB stages, PK‐resistant α‐synuclein had a higher positive rate than psyn.

Conclusion: PK‐resistant α‐synuclein is more sensitive than psyn. These findings suggest that skin biopsies with PK‐pretreated α‐synuclein antibody is a useful tool in the diagnosis of LBD. We will further investigate by increasing the number of cases.

P2‐59

Diffuse Lewy Body Disease coexisting with Progressive Supranuclear Palsy pathology and partially co‐localising tau and alpha‐synuclein positive oligodendroglial inclusions

Annelies Quaegebeur¹; Sarah Mueller²; Claire Troakes²; Istvan Bodi^1,2

¹Clinical Neuropathology, Kings College Hospital NHS Foundation Trust, London, UK; ²MRC London Neurodegenerative Diseases Brain Bank, IOPPN, Kings College London, SGDP Centre, London, UK

Introduction: Neuronal alpha‐synuclein deposits are the hallmark lesions of Diffuse Lewy Body disease (DLBD) whereas glioneuronal 4‐repeat‐tau accumulation defines Progressive Supranuclear Palsy (PSP). Rare cases of coexisting DLBD and PSP have been described, but the oligodendroglial pathology remains underappreciated in DLBD.

Clinical summary: A brain bank donation from a 71 years old male was examined. He was diagnosed with Parkinsons disease 16 years ago and developed hallucinations, confusion and autonomic failure 6 years ago.

Pathological findings: Histology showed widespread alpha‐synuclein immunoreactive Lewy bodies and Lewy neurites in keeping with a mild neocortical subtype of DLBD. In addition there was prominent tau pathology with tangles, oligodendroglial coiled bodies and tufted astrocytes, showing selective tau‐4‐repeat immunoreactivity, in basal ganglia, midbrain and tectum of the pons. Interestingly, alpha‐ynuclein positive oligodendroglial inclusions were also seen, especially commonly in the pallidothalamic tract and the midbrain. These inclusions did not show the distribution and typical morphology of Papp‐Lantos bodies seen in Multiple System Atrophy. Double immunofluorescence studies showed that some of these oligodendroglial alpha‐synuclein inclusions co‐localised with tau‐positive coiled bodies.

Conclusion: Concurrent alpha‐synucleinopathy in a minority of PSP cases and DLBD with PSP‐like pathology has been described separately. However, partial co‐localisation of tau and alpha‐synuclein in oligodendroglial inclusions in mixed DLBD and PSP pathology has not been previously demonstrated. The findings raise the question whether there is a pathogenic interaction between these distinct pathologies rather than a coincidental overlap.

P2‐60

An autopsy case of mitochondrial complex III deficiency with homozygous mutation c.157_158dup in TTC19 clinically presenting as spinocerebellar ataxia

Ryoko Takeuchi¹; Etsuko Fujisawa^1,2; Hidehiro Shibayama¹; Fumiaki Katada¹; Susumu Sato¹; Shigeo Murayama³; Toshio Fukutake¹

¹Kameda Medical Center; ²Toukatsu Hospital; ³Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Objective: To document the autopsy findings in a case of homozygous mutation c.157_158dup in TTC19 manifesting clinical features of spinocerebellar atrophy.

Clinical summary: A 15‐year‐old Japanese male with sub‐average intelligence and questionable consanguinity developed gait disturbance with dragging of the left foot. At the age of 38, he showed dysarthria and could walk only with assistance. He was admitted to our hospital at age 60. Neurological examination disclosed saccadic eye movements, gaze‐evoked directional nystagmus, severely slurred speech, mild muscular weakness in the lower legs, and truncal and limb ataxia. The mini‐mental state examination score was 0/30. Brain MRI demonstrated cerebellar atrophy and abnormal intensity in the bilateral putamen. Spinocerebellar ataxia was clinically diagnosed. Six months later, the patient died of pneumonia at age 61. His elder brother and two of his elder sisters had also shown gait disturbance and died in their forties or fifties.

Results: The brain weighed 1370 g before fixation. The cerebellum showed diffuse atrophy with brownish discoloration of the deep white matter. The bilateral striatum was severely degenerated. Histologically, the cerebellar white matter, striatum and tegmentum of the brainstem showed symmetrical cystic changes with fibrillary gliosis and capillary proliferation. The inferior olivary nuclei and substantia nigra showed asymmetrical degeneration. The cerebellum showed severe Purkinje cell loss and Bergmann's gliosis. Genetic analysis using full exome sequencing revealed homozygous mutation c.157_158dup in TTC19, known to cause mitochondrial complex III deficiency.

Conclusions: For differential diagnosis of spinocerebellar ataxia, TTC19 mutation should be included as a rare possibility.

P2‐61

Early central nervous system involvement in a V30M ATTR amyloidosis patient

Ricardo Taipa¹; Ana Martins Silva²; Luisa Lobato³; Ramon Viscaino⁴; Jose Eduardo Alves⁵; Teresa Coelho²; Manuel Melo Pires¹

¹Neuropathology Unit, Department of Neurosciences, Centro Hospitalar do Porto; ²Unidade Corino de Andrade, Department of Neurosciences, Centro Hospitalar do Porto; ³Nephrology Department, Centro Hospitalar do Porto; ⁴Anatomic Pathology Department, Centro Hospitalar do Porto; ⁵Neuroradiology Department, Centro Hospitalar do Porto

Introduction: Hereditary ATTR amyloidosis is a systemic amyloidosis caused by transthyretin (TTR) gene mutation. Patients with V30M gene mutation, the most common mutation worldwide, typically present a severe sensorimotor and autonomic polyneuropathy and rarely develop CNS symptoms. CNS involvement has been recently described in posttransplant patients, whose transplant extend their life expectancy, and older symptomatic patients. We report a young female patient with a symptomatic ATTR cerebral amyloid angiopathy (CAA).

Methods: Clinical case retrospective analysis.

Results: A 41‐year‐old female, V30M TTR carrier presented with severe nephrotic syndrome by the age of 38. The neurological examination at this point showed minor abnormalities consistent with small fiber neuropathy. Kidney biopsy revealed severe TTR amyloid deposition with negative immunoglobulins and complement deposition and the patient started treatment with TTR stabilizer (tafamidis). Three years later the patient reported transient focal neurological episodes (FNEs) (numbness of left face and arm; right arm paresthesia progressing rapidly to the right hemiface). Brain MRI showed subcortical white matter hyperintensities and subpial hypointense lesions in T2* sequencing suggestive of hemorrhagic nature. She had high ESR and anti‐nuclear antibodies titles. A brain biopsy was performed to exclude CNS vasculitis and revealed severe leptomeningeal ATTR‐CAA. The study for amyloid‐beta showed small diffuse cortical deposits, with no vascular involvement. Patient was APOE4 homozygous.

Conclusions: ATTR amyloidosis with V30M can have a severe and early CNS involvement. The relationship between different TTR mutations and clinical phenotype, and phenotypical variability within the same mutation remains unclear.

P2‐62

Hereditary diffuse leukoencephalopathy with spheroid axons (HDLS): clinical and neuropathological analysis

Chenhui Mao¹; Liangrui Zhou²; Lixin Zhou¹; Yingmai Yang¹; Haitao Ren¹; Yanhuan Zhao¹; Bin Peng¹; JIng Gao¹; Yupu Guo¹

¹Department of Neurology, Chinese Academy of Medical Science/ Peking Union Medical College Hospital; ²Department of Pathology, Chinese Academy of Medical Science /Peking Union Medical College Hospital

Introduction: HDLS is an autosomal dominant inherited rare disease. The clinical manifestation includes cognitive disorder, movement disorder et al. The white matter changes on MRI are sometimes nonspecific. Characteristic histology is white matter damage with spheroid axons and pigmented macrophages. CSF1R was the pathologic gene mutation.

Methods: 5 patients diagnosed HDLS with brain biopsy and/or gene analysis were collected and clinical history, neuroimaging, histology as well as genetic information were analyzed and compared.

Results: 4 females and 1 male aged 25‐47 year old were included. The durations of the disease varied from 9 months to 4 years. Clinical manifestations include cognitive disorder with or without psychiatric and behavior problems, movement disorders such as paralysis, parkinsonism, pyramidal tract destruction as well as dysarthria and numbness of limbs. MRI showed multiple peri‐ventricular white matter lesions, some of which fused to patches. There was no enhancement of the lesions, but DWI hyper‐intensity was obvious and persistent. Brain biopsy was done in 4 of them. Histology showed widespread white matter damage, especially axon destroy with spheroids axons which were stained by NF and Ub, but not Aβ and Tau. Macrophages accumulation with foamy and pigmented cytoplasm was seen. Neither inflammation nor demyelization was found. CSF1R mutation was found in 3 of them.

Conclusion: Small peri‐ventricular white matter lesions in young dementia patients should be appreciated. Persistent DWI hyper‐intensity of the lesion on MRI was typical. Characteristic histology and gene analysis were diagnosable.

P2‐63

Manipulation of retinal glutamate levels by overexpression of GLAST reduces retinal ganglion cell death in an experimental model of glaucoma

Atsuko Kimura; Kazuhiko Namekata; Xiaoli Guo; Yuriko Azuchi; Chikako Harada; Takayuki Harada

Visual Research Project, Tokyo Metropolitan Institute of Medical Science

Introduction: Glaucoma is a neurodegenerative disease of the eye and we are interested in protection of retinal ganglion cells (RGCs), a type of retinal neurons whose death causes blindness in glaucoma. In this study we have generated mice with overexpression of the glutamate aspartate transporter (GLAST) with the aim to examine if efficient removal of extracellular glutamate protects RGCs in an experimental model of glaucoma, the optic nerve injury (ONI) model.

Methods: A novel transgenic mouse line with overexpression of GLAST (GLAST Tg) was generated. GLAST Tg mice were healthy and viable. Following ONI, changes in retinal morphology was monitored in vivo by optical coherence tomography (OCT). The number of RGCs was determined by haematoxylin & eosin staining and retrograde labelling of RGCs.

Results: Increased GLAST expression in the retina was confirmed by western blotting. In vivo imaging by OCT showed that the thickness of the ganglion cell complex in GLAST Tg mice was greater than in WT mice following ONI. Consistently, the ONI‐induced RGC death in GLAST Tg mice was lower than in WT mice. We found that the retinal oxidative stress level is suppressed in GLAST Tg mice compared with WT mice after ONI.

Conclusion: Modulation of glutamate levels in the retina is effective for preventing RGC death. Increasing GLAST function in the retina may be useful for treatment of glaucoma.

P2‐64

Microglia loss does correlate with axonal spheroids in adult‐onset leukoencephalopathy with axonal spheroids

Murad Alturkustani^1,2,3; Lee‐Cyn Ang^2,3; Qi Zhang^2,3; Basma AlYamany^2,3

¹Department of Pathology, King Abdulaziz University, Jeddah, Saudi Arabia; ²London Health Sciences Centre, London, Ontario, Canada; ³University of Western Ontario, London, Ontario, Canada

Introduction: The pathogenesis of adult‐onset leukoencephalopathy with axonal spheroids (ALAS) is debatable. Pathological studies have suggested a primary axonopathy with secondary demyelination. However, with the identification of mutations in CSF1R, which is important for microglial survival, ALAS has been considered as microgliopathy. In this study, we examine the correlation of microglial changes and axonopathy in ALAS.

Methods: A total of 6 ALAS cases were studied. The white matter lesions were classified into 3 evolving stages: 1) white matter with numerous axonal spheroids in a background of well‐myelinated fibers; 2) moderate loss of myelinated fibers with or without axonal spheroids; and 3) leukodystrophy‐like pattern of severe confluent axonal and myelin loss. Digital images of these stages were taken using the Aperio system. Precise areas of interest from the digital images stained with LFB/HE, APP, HLA‐DR, and NF were demarcated on the computer screen. The spheroids and the ramified microglia (HLA‐DR) were semi‐quantified and assigned score from 0‐3.

Results: We found a strong correlation between the preponderance of axonal spheroids and degree of microglia loss. In all areas with predominance of axonal spheroids, there is almost complete loss of ramified microglia (score 0‐1). This finding is also apparent even in very small affected areas in the cortex and the white matter. Meanwhile cells with macrophage phenotype are present in Stage 2 and 3 but not in the Stage 1.

Conclusions: Axonal pathology (i.e. axonal spheroids) is strongly associated with loss of ramified microglia, suggesting a morphological‐genetic correlation in the pathogenesis of ALAS.

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A 43‐year‐old male autopsy case of sporadic amyotrophic lateral sclerosis with a family history of spinocerebellar ataxia type 3/Machado‐Joseph disease

Shuji Hirata¹; Ayumu Noji¹; Makiko Kobayashi²; Kouichi Honma³; Shigeo Murayama⁴

¹Department of Neurology, Awa Regional Medical Center; ²Department of Neurology, Tokyo Medical University; ³Department of Pathology, Kameda Medical Center; ⁴Elderly Brain Bank, Tokyo Metropolitan Hospital and Institute of Gerontology

Introduction: The cause of amyotrophic lateral sclerosis (ALS) is still unknown. Transactivation response DNA binding protein 43 kDa (TDP‐43) is, however, thought to play a pathomechanistic role of ALS and also found in spinocerebellar ataxia type 3/Machado‐Joseph disease (SCA3/MJD). We report an autopsy case of sporadic ALS with a family history of SCA3/MJD.

Clinical summary: The patient had a weakness of right leg at 41, followed by gait disturbance, weakness of arms, and dyspnea successively, and then admitted to our hospital at 43. His relatives had spinocerebellar ataxia, and his mother had been diagnosed with SCA3/MJD by gene examination. Physical examination revealed flaccid tetraparesis, fasciculaions on extremities, and areflexia of both legs. He didn't have ophthalmoparesis, ataxia, or sensory disturbance. Intramuscular electromyography findings indicated systemic neuropathic changes. ALS was most suspected but not determined because he had no upper motor neuron signs. Considering inflammatory neuropathies, steroid puls therapy and intravenous immunoglobulin were performed but didn't succeed. He died of dyspnea 2.5 months later after admission.

Pathological findings: Atrophies were observed at oculomotor, trochlear, abducent, and hypoglossal nerves, and ventral roots. Neuronal loss and gliosis were observed in trigeminal motor nuclei, trochlear and hypoglossal nuclei, and spinal anterior horns. Degenerations were observed in corticospinal tracts. Bunina body was found in remaining thoracic anterior horn cells. TDP‐43 were found in spinal anterior horns, hypoglossal nuclei, and primary motor area. 1C2 immunoreactive intranuclear inclusions were found in pontine nuclei.

Conclusion: We reported an autopsy case of sporadic ALS with neuropathological findings of SCA3/MJD.

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Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS‐like disease

Thomas Brannstrom¹; Peter M Andersen²; Johan Bergh¹; Elaheh Ekhtiari Bidhendi¹; Stefan M Marklund¹

¹Department of Medical Biosciences, Umea University; ²Department of Pharmacology and Clinical Neurosciences, Umea University

Mutations in superoxide dismutase‐1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). ALS patients and transgenic model mice carrying mutant human SOD1 (hSOD1) develop aggregates of the protein in motor neurons. Previously we showed that in transgenic mice two strains of aggregates (denoted A and B) can arise. Inoculation of minute amounts of A or B aggregate seeds, prepared by centrifugation through a density cushion, into spinal cords of asymptomatic G85R‐hSOD1 transgenic mice initiated spreading, exponentially growing templated hSOD1 aggregations concomitantly with premature fatal ALS (Bidhendi EE et al, JCI 2016). In contrast to the unstable G85R‐hSOD1 variant mentioned above the D90A‐hSOD1 mutation produces a stable protein with an essentially normal enzymatic activity (Andersen et al, Nat Gen 1995). Transgenic mice for the mutation are known to lose motoneurons. However, only homozygous mice die of ALS after an extended clinical course. Heterozygous D90A mice showed much less and later pathologic changes, with lifespans of 680 days. Herein we show that inoculation of the strain A and B seeds into lumbar spinal cord of heterozygous hSOD1 D90A tg mice at the age of 100 days resulted in premature fatal ALS‐like disease around 250 and 350 days after inoculation, respectively. While control seeds inoculated mice or mice which had not been inoculated, became terminally ill after around 690 days. This supports our previous proposition that prion‐like templated spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic models, but also in hSOD1‐induced ALS in man.

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Involvement of TGF‐beta signaling‐related proteins in formation of inclusions of adult‐onset neuronal intranuclear inclusion disease

Tomoe Sato^1,2; Mari Tada¹; Yasuko Toyoshima¹; Mari Yoshida³; Itsuro Tomita⁴; Koichi Wakabayashi⁵; Kenji Yoshida⁶; Osamu Onodera²; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neurology, Brain Research Institute, Niigata University, Niigata; ³Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute; ⁴Department of Neurology, Nagasaki Kita Hospital, Nishisonogi, Nagasaki; ⁵Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki; ⁶Department of Neurology, Fukushima Medical University, Fukushima

Objective: To clarify the significance of TGF‐β‐related proteins in formation of nuclear inclusions (NIs) in adult‐onset neuronal intranuclear inclusion disease (NIID).

Methods: We examined cerebral cortex (autopsied 5; biopsied 1) from 6 patients diagnosed pathologically as having NIID with CNS symptoms (symptomatic group) and 3 autopsied patients without CNS symptoms but having similar NIs (non‐symptomatic group), as well as abdominal adipose tissue from 3 patients in each group, and skin biopsy specimens from another 7 patients with symptomatic NIID. We identified NIs by p62 immunolabeling, and performed double‐labeling immunofluorescence for p62 and pSmad2/3 or Smurf2.

Results: Glia with NIs appeared denser than neurons with NIs (p < 0.01), and no significant inter‐group difference was evident (p = 0.95 for glia; 0.33 for neurons). All nuclei without NIs showed labeling for pSmad2/3. However, in the symptomatic and non‐symptomatic groups, 16.0% and 13.9% of nuclei with NIs, respectively, showed no pSmad2/3 labeling, and these proportions were similar (p = 0.91). The proportion of Smurf2 and p62 double‐labeled NIs in the cortex in the symptomatic group was significantly higher than that in the non‐symptomatic group (76.0% and 28.0%, respectively, p < 0.01), and the proportions in the adipose tissue of both groups were not different (93.3% and 34.0%, respectively, p = 0.01). In the symptomatic individuals the proportions in the cortex (76.0%) and skin (87.5%) were similar.

Conclusions: Thus, characteristic expression profiles of pSmad2/3 and Smurf2 suggests a role for the TGF‐β‐related proteins in the formation of NIs in adult‐onset NIID.

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The expression of CD3, oxidative cytotoxic molecule, and stress response proteins related to degeneration of Purkinje cells in multiple system atrophy, cerebellar type

Masako Kato¹; Shinsuke Kato²; Kazuhiko Hayashi¹; Kiyota Kato³; Lusi Oka Wardhani¹

¹Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine; ²Division of Neuropathology, Department of Pathology, Tottori University Faculty of Medicine; ³School of Medicine, Hiroshima University

Introduction: The pathogenesis of multiple system atrophy, cerebellar type (MSA‐C) remains unknown. MSA‐C is characterized by damage mainly to cerebellum, especially Purkinje cells. The expression of CD3 as a marker for the morphological and functional analysis of cerebellar Purkinje cells, and the expression of oxidative cytotoxic or protective molecules of the Purkinje cells under MSA‐C stress were studied.

Methods: This study was carried out on brain tissues from 17 patients with MSA‐C, 10 normal individuals and from 19 fetuses, three neonates, and eight infants. For immunohistochemical analyses the following primary antibodies were used: CD3, oxidative modification to cysteine sulfonic acid of cys111 in human copper‐zinc superoxide dismutase (Ox‐SOD1), and stress response proteins (SRPs) (27, 70 and 90).

Results: In normal adult Purkinje cells, the cell bodies and dendritic arborization including primary to tertiary dendrites were positive to CD3. The statistical quantitative analysis revealed that the areas positive for CD3 in MSA‐C disappeared in the order from tertiary dendrites toward the cell bodies, along with the disease progression. The CD3‐expression pattern along with MSA‐C disease progression was reverse to the development changes in CD3‐expression pattern of Purkinje cells from fetus to adults. The Purkinje cells in MSA‐C were positive to Ox‐SOD1 and SRPs, although normal Purkinje cells from fetus to adult were negative.

Conclusion: Purkinje cells in MSA‐C were under control of oxidative cytotoxic or protective molecules, and were finally impaired from periphery toward the center of the Purkinje cell arborization, being reverse to development from fetal to infant on the CD3 expression.

P2‐69

Clinico‐pathological analysis in two cases of Huntington's disease

Koushun Matsuo¹; Yohei Hosokawa²; Hiroki Takahashi^3,4; Chihiro Fujii^1,3; Kiyonori Miyata¹; So Tando⁴; Toshiki Mizuno³; Kyoko Itoh⁴

¹Division of Neurology, Ohmihachiman Community Medical Center; ²Division of Pathology, Ohmihachiman Community Medical Center; ³Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine; ⁴Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

Introduction: Huntington's disease (HD) is neurodegenerative disease presenting chorea, dementia and other psychiatric symptoms. We analyzed clinico‐pathological features in two cases of HD.

Clinical summary: Case 1 was 79‐year‐old woman at death. Her father and one brother had similar symptoms. The initial symptom was chorea at the age of 74. After 4 years from the onset, she was diagnosed as HD. The number of CAG repeats was 41. Total clinical course was about 5 years. Case 2 was 66‐year‐old man at death. The initial symptom was change of character at the age of 53. His father, sister and nephew had similar symptoms. After 3 years from the onset, he was diagnosed as HD. The number of CAG repeats was 49. Total clinical course was about 13 years.

Pathological findings: As common findings in Case 1 and 2, severe atrophy of caudate nucleus and putamen were noted with marked neuronal loss and intense gliosis. Immuno‐histochemistry for the expanded polyglutamine (IHC for polyQ) revealed that dense intra‐nuclear and granular intracytoplasmic inclusions were distributed in neurons in the central nervous system, including cerebral cortex, thalamus, pons, dentate nucleus.

Conclusion: These two cases with HD were supposed to be caused by paternal transmission, although the age of onset was not young. The patterns of IHC for polyQ might shed light on the pathogenesis of our cases.

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An autopsy case of late‐onset slowly progressive spastic paraplegia with a large deletion mutation in KIAA0196

Akira Arakawa¹; Masanori Kurihara¹; Terunori Sano²; Teppei Morikawa³; Masako Ikemura³; Hiyoruki Ishiura¹; Jun Shimizu¹; Shigeo Murayama⁴; Yuko Saito²; Tataushi Toda¹

¹Department of Neurology, the Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; ²Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; ³Department of Pathology, the Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; ⁴Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institution of Gerontology, Tokyo, Japan

Introduction: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disorder characterized by spasticity and weakness of the lower limbs. The typical pathology is dying back‐ type chronic degeneration of bilateral corticospinal tracts of the spinal cord.

Case: A 77‐year‐old man with a 16‐year history of slowly progressive spastic paraparesis was admitted due to infective endocarditis. He was known to have a large deletion in KIAA0196, which is the causative gene of hereditary spastic paraplegia type 8 (SPG8). He died of multiple organ failure and autopsy was performed.

Pathological findings: The brain weighted 1,162 g. Multiple ischemic infarcts were detected mainly in the right middle cerebral artery territory. The Betz cells were preserved. Secondary degeneration from the recent infarcts involved the right medullary pyramis and the left cervical corticospinal tracts. Distinct from these recent changes, caudally accentuated mild pallor with myelin stain of bilateral pyramidal tracts was evident. Histologically, the lesion showed commensurate loss of axons without evident astrocytic or microglial reaction. This pathology is consistent with his clinical picture and typical for HSP.

Conclusion: We report the first autopsy case of SPG8 with a large deletion in KIAA0196. Further autopsy studies may be required to elucidate the relationship between genetic abnormality and clinical and pathological phenotypes in HSP.

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Amyotrophic lateral sclerosis and parkinsonism‐dementia complex of the Hohara focus of the Kii Peninsula : pathological findings as a multiple proteinopathy

Maya Mimuro¹; Mari Yoshida¹; Yasushi Iwasaki¹; Ryogen Sasaki²; Shigeki Kuzuhara³; Yasumasa Kokubo⁴

¹Institute for Medical Science of Aging, Aichi Medical University; ²Department of Neurology, Kuwana City Medical Center; ³School of Nursing, Suzuka University of Medical Science; ⁴Graduate School of Regional Innovation Studies, Mie University

Introduction: The high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia complex (PDC) has been known in the Kii Peninsula of Japan and on Guam. The recent reports have revealed accumulation of several proteins in the brains of patients with ALS/PDC on Guam.

Methods: We neuropathologically examined the brains and spinal cords of 18 patients with Kii ALS/PDC (clinical diagnoses: 8 ALS and 10 PDC) in Hohara Village, the eastern focus of Kii ALS. Sections of these specimens were immunohistochemically stained with antibodies against four major proteins: tau, trans‐activation response DNA binding protein 43 kDa (TDP‐43), alpha‐synuclein (αSyn) and beta/A4 amyloid (Aβ).

Results: Tau pathology including neurofibrillary tangles and TDP‐43‐positive inclusions were observed in all 18 cases, mainly in the limbic system. Synuclein pathology was present in 14 cases (77.8%) and Aβ was accumulated in 13 cases (72.2%). Several neurons contained two or more proteins. They were pathologically classified into three subtypes according to the most prominent proteinopathy: the tauopathy‐dominant type, the TDP‐43 proteinopathy‐dominant type, and the synucleinopathy‐dominant type. Three subtypes shared the common characteristic tau pathology, which suggests they are pathologically continuous on a spectrum and different phenotypes of a single disease.

Conclusion: We have concluded that ALS/PDC in the Hohara focus of the Kii Peninsula is a single disease characterized neuropathologically by multiple proteinopathy with tau dominancy. Whether the coexistence of the three proteinopathies was incidental or pathogenetically related remains to be clarified.

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Isolated nigral degeneration not associated with a‐synuclein pathologies in the familial Parkinson's disease with LRRK2 p.R1441H mutation

Masashi Takanashi¹; Manabu Funayama²; Kenya Nishioka²; Daisuke Taniguchi²; Takashi Ogawa²; Sho Tsuyama³; Nobutaka Hattori²

¹Dept. of Neurology Juntendo Koshigaya Hospital; ²Dept. of Neurology Juntendo University School of Medicine; ³Dept. of Human Pathology Juntendo University School of Medicine

Introduction: More than ten causative genes of hereditary Parkinson's disease (PD) were detected. LRRK2 is a causative gene for autosomal dominant familial PD.Their pathologies are very heterogeneous. Here we report the neuropathologies of familial PD with LRRK2 p.R1441H homozygous mutation in the region of southern Japan.

Clinical summary: The patient was 74 years‐old man. His parents were consanguineous marriage, and four of his siblings were PD. There was another family had members of PD in the same city. He was diagnosed PD at the age of 60 and medicated with levodopa. Response of levodopa was quite good, but diurnal fluctuation, levodopa induced dyskinesia appeared. He became bed‐ridden on 73yo, and died of severe pneumonia.

Pathological findings: Depigmentation of the substantia nigra (SN) was remarkable. Neuronal loss and gliosis only in the SN were observed. There were no Lewy pathologies and other pathological structures. The neuropathological feature of this PD was isolated nigral degeneration without Lewy pathologies (IND without LP). The pathologies of the autopsied case of another family with LRRK2 p.1441H heterozygous mutation also showed same findings (data not shown).

Conclusion: This is the new pathological phenotype of familial PD with LRRK2 p.R1441H mutation.Among pathologies of LRRK2 mutated PD, IND without LP were reported in the families with LRRK2 p.I2020T mutation. The cases with homozygous and heterozygous LRRK2 p.R1441H mutation showed also IND without LP.This is the new pathological variation caused by LRRK2 p.R1441H mutations.

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Immunohistochemical Analysis of Nna1 in the Ataxia and Male Sterility (AMS) Mouse, an Nna1 Mutant and Model of Cerebellar Ataxia

Asuka Araki¹; Pang Bo¹; Koji Omura¹; Chika Sakai³; Yu Yamanashi³; Abdullah Mohammed Sheikh²; Atsushi Nagai²; Takayuki Harada^1,4; Riruke Maruyama¹

¹Departments of Pathology, Shimane University School of Medicine; ²Departments of Laboratory Medicine, Shimane University School of Medicine; ³Fourth‐Year Medical Student, Shimane University School of Medicine; ⁴Masuda Medical Association Hospital

Introduction: Nna1 is phylogenetically‐preserved and codes for cytosolic carboxypeptidase 1. Different Nna1 mutations are known to cause the progressive loss of Purkinje cells (PCs); thus models of cerebellar ataxia, and different modes of cellular degeneration/loss depend on the cell types. Our AMS mouse harbors a point mutation and is the only Nna1‐allele model for which the genotype can be determined through a combination of restriction‐enzyme digestion and PCR. We applied immunohistochemistry using anti‐human Nna1 antibody to investigate its distribution in the cerebellum of AMS mice of each genotype from postnatal days (P) 7‐28.

Results: 1. Both the molecular and granular layers were positive for Nna1 in wild‐type mice. The positivity peaked on postnatal day P7, before the maturation of the PC dendrites, and decreased thereafter. The PC somata and dendrites were clearly positive on P15, when dendritic innervation starts by the climbing fibers, to P28. 2. In ams‐homozygous mice, PCs showed the same positive pattern as the wild‐type mice. The semi‐quantification of the Nna1's stain‐strength revealed in the following order: wild‐type, ams‐heterozygous, then ams‐homozygous.

Conclusion: The distribution of the Nna1 in the cerebellum, except in the PCs, of wild‐type mice varies according to the age of the mice, while that in the PCs is stable from P15. The Nna1‐mutated protein is present in AMS heterozygous or homozygous mice. The loss of PCs in homozygous AMS might occur due to a protein shortage because due to the instability of its 3‐dimensional structure, which is caused by the point mutation.

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Brainstem calcification and extensive white matter changes in an autopsy case of bilateral striopallidodentate calcification with Alzheimer's disease

Tamaki Iwase¹; Mari Yoshida²; Ikuru Yazawa³

¹Dept. of Neurol., Nagoya City Koseiin Medical Welfare Ctr.; ²Inst. for Med. Sci. of Aging, Aichi Medical Univ.; ³Lab. of Res. Resources, Res. Inst., Natl. Ctr. for Geriatrics and Gerontology

Introduction: Bilateral striopallidodentate calcification, also known as Fahr's syndrome, is a rare but well‐known neurological disorder characterized by extensive symmetrical brain calcification, specifically in the basal ganglia and cerebellar dentate nuclei. In most cases, brain calcification is detected by computed tomography; thus the brainstem calcification and white matter changes have not been described well.

Clinical summary: The patient suffered from dysarthria diagnosed as cerebrovascular insufficiency with cerebral calcification at 65 years of age. She developed mild dementia at 75 years of age and Parkinsonism at 76 years of age. She became assisted with daily activities at 77 years of age. She became severely demented and a bed‐ridden state at 82 years of age. She survived two years with tube feeding and died of lung cancer at 85 years of age. Computed tomography revealed symmetrical extensive intracranial calcification and severe cerebral atrophy, however, brainstem calcification was not detected.

Pathological findings: Alzheimer's disease pathology and massive vascular calcification in the basal ganglia and dentate nuclei of the cerebellum were found. In addition, the vascular calcification continuously spread over the surrounding white matter and occasionally into the cortex (the depths of cerebral cortical sulci and cerebellar folia). In the brainstem, the calcification was extensive in the medulla and pontine tegmentum.

Conclusion: We found severe vascular calcification in the brainstem. We also clarified the continuity of the vascular calcification through the white matter to the cortex. We should recognize brainstem calcification and extensive white matter changes in bilateral striopallidodentate calcification.

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Amyloid beta‐induced lysosomal impairment in retinal pigment epithelium contributes to the pathogenesis of dry age‐related macular degeneration

Jeong Hun Kim^1,2; Dong Hyun Jo¹; Hyoung Oh Jun¹; Jin Hyoung Kim¹

¹Fight against Angiogenesis‐Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital; ²Department of Ophthalmology & Biomedical Sciences, College of Medicine, Seoul National University

We have reported that Intracellular amyloid beta (Aβ) in retinal pigment epithelium (RPE) has been implicated in the pathogenesis of age‐related macular degeneration (AMD). Herein we demonstrate that lysosomal impairment by Aβ contributes to autophagic cell death in RPE as a possible pathogenesis of dry AMD. First we found out that intracellular Aβ induces non‐apoptotic cell death in a dose dependent manner. Dysfunction of autophagic flux by Aβ leaded to autophagic cell death. In addition, Aβ induced lysosomal depletion as well as mitochondrial depletion. Inhibition of Aβ uptake by blocking RAGE or enhancement of autophagic flux with rapamycin effectively rescued RPE from Aβ induced cell death. In vivo, intravitreal injection of Aβ induced autophagy and cell death. Rapamycin prevents Aβ induced RPE degeneration in mouse. In conclusion, Aβ induced dysregulation of autophagy (lysosomal impairment) and autophagic cell death in retinal pigment epithelium. We suggested autophagic dysfunction by Aβ as a pathogenesis of dry AMD.

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Dry age‐related macular degeneration like pathology in aged 5XFAD mice: Ultrastructure and microarray analysis

Jin Hyoung Kim¹; Young‐Hoon Lee²; Jeong Hun Kim^1,3

¹Fight against Angiogenesis‐Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital; ²Department of Oral Anatomy, School of Dentistry, Chonbuk National University; ³Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine

Extracellular deposit of amyloid beta (Aβ) is a common pathologic feature in both age related macular degeneration (AMD) and Alzheimer disease, but the role of intracellular Aβ on the tight junction of the retinal pigment epithelium (RPE) had not been well investigated. Recently, we reported that intracellular Aβ42 could play a role in the breakdown of the outer blood retinal barrier in 5XFAD mice. Based on our hypothesis that 5XFAD mice, an animal model of Alzheimer disease, presents an accelerated accumulation of Aβ in the eyes as well as the brain could be a mouse model of dry AMD, we found out that aged 5XFAD mice can be used for dry AMD mouse model. The ultrastructure of RPE of 5XFAD mice was analyzed using transmission electron microscopy. Of importance, the aged 5XFAD mice show ultrastructural changes in the RPE and Bruch membrane (BM) that are compatible with the cardinal features of human dry AMD, including a loss of apical microvilli and basal infolding of the RPE, increased BM thickness, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment laden phagosomes. In microarray based analysis, the RPE complex of the aged 5XFAD mice shows differential gene expression profiles consistent with dry AMD in the inflammation response, immune reaction pathway, and decreased retinol metabolism. Taken together, we suggest that aged 5XFAD mice can be used as a mouse model of dry AMD to study Aβ related pathology and develop a new therapeutic approaches.

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The role of KIF1C in sustainable myelination in SPG58/SAX2

Khalid El Hachimi; Anne Vaiman; Magali Frah; Olivier Albaric; Alexis Brice; Frederic Darios; Jean‐Luc Vilotte; Giovanni Stevanin; Didier Boichard; Amandine Duchesne

EPHE/CNRS UMR 7225 ‐ Inserm U 1127 ‐ UPMC‐P6 UMR S 1127 Institute of Brain and spinal cord, Paris

Hereditary spastic paraplegias (HSPs) are heterogeneous human neurodegenerative diseases., Mutations of genes encoding motor kinesins have been involved in various HSP isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58/SAX2). Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock‐out, therefore mimicking mutations in humans affected by SPG58/SAX2. The functional consequences of KIF1C loss of function in cattle were also histologically evaluated. We showed that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. The lesions were associated with abnormal extension of paranodal sections. This model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young‐adult Charolais cattle. This model provides useful information for SPG58/SAX2 disease and other demyelinating lesions.

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An autopsy case of SPG11 with peculiar p62‐immunopositive intracytoplasmic inclusions

Shinichirou Mori¹; Akihiro Watanabe²; Masahiro Shijo¹; Hiroyuki Honda¹; Satoshi O Suzuki¹; Naokazu Sasagasako²; Toru Iwaki¹

¹Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University; ²NHO Omuta National Hospital

Introduction: SPG11 is an autosomal recessive inherited spastic paraplegia with thin corpus callosum. Biallelic mutation in the SPG11 gene can also cause juvenile‐onset amyotrophic lateral sclerosis‐5 (ALS5) and Charcot‐Marie‐Tooth disease type 2X (CMT2X), different neurodegenerative disorders with overlapping features. Here, we report an autopsy case of SPG11 with IVS18+1G>T homozygous mutation.

Clinical summary: At 27 years of age, the patient developed lower limb spasticity, and the symptom gradually worsened. Her elderly brother also suffered to same symptom. By age 44 years, she was wheelchair‐bound and severely demented. She died of esophageal perforation at the age of 57 years. A cardiac uptake of 123I‐metaiodobenzylguanidine is reduced, suggesting the cardiac sympathetic denervation.

Autopsy findings: The brain weighed 786g. Severe cerebral atrophy and thin corpus callosum were noted. Histologically, large intracytoplasmic eosinophilic granular structures with vacuoles were observed in spinal root ganglia. Many coarse eosinophilic granules are also noted throughout the CNS. These eosinophilic structures are highlighted by immunohistochemistry for p62, but negative for p‐TDP43 and p‐tau. Additionally, rather small p‐TDP43 positive neuronal inclusions are observed in the brain and spinal cord, however, no skein‐like inclusions were detected. Neuronal loss of substantia nigra was severe. Tyrosine hydroxylase‐positive nerve fibers were markedly diminished at the pericardium.

Conclusion: The autopsy findings demonstrated that SPG11 involved widespread neuronal structures: cerebral cortex, corticospinal tracts, extrapyramidal nuclei, and peripheral nervous system including sympathetic nerves. Large eosinophilic bodies in the spinal ganglion cells with vacuoles may be most notable characteristic feature of SPG11. p‐TDP43 depositions were also widely observed.

P2‐79

Selective autophagy eliminates ALS‐related mutant SOD1 protein in cultured microglia

Motoko Kawaguchi Niida¹; Fujiko Tsukahara²; Norihiro Sudou³; Tomoko Yamamoto¹; Makoto Sawada⁴; Kazuhiko Watabe⁵; Noriyuki Shibata¹

¹Department of Pathology, Tokyo Women's Medical University; ²Department of Pharmacology, Tokyo Women's Medical University; ³Department of Anatomy, Tokyo Women's Medical University; ⁴Department of Brain Functions, Nagoya University; ⁵Department of Medical Technology, Kyorin University

Background: Gain‐of‐toxic function of mutant SOD1 protein is thought to be responsible for motor neuronal death and formation of aggregates or inclusions in motor neurons and astrocytes. However, there is currently no available data on how microglia, in contrast to motor neurons and astrocytes, remain spared from mutant SOD1 toxicity and aggregate formation.

Methods: We generated pcDNA3‐Venus‐tagged human wild‐type and fALS‐related A4V and G93A mutant SOD1 constructs. We then transfected these plasmids to mouse microglial cell line and examined their effects on cell toxicity and aggregate formation by immunohistochemistry, western blot and ELISA.

Results: Immunocytochemistry showed that the transfected fALS‐related mutant SOD1 proteins were barely detectable, whereas transfected wild‐type SOD1 proteins were detected in cultured microglia. Westernblot and ELISA analyses revealed that mutant SOD1 protein levels were markedly reduced compared to those of wild‐type SOD1 in microglia. The levels of mutant SOD1 protein were increased by the treatment with autophagy inhibitors. Immunocytochemistry showed that wild‐type SOD1 protein was expressed in the cytoplasm and nucleus, whereas mutant SOD1 proteins were colocalized with the autophagy‐related proteins p62 and LC3. Moreover, colocalization of these mutant SOD1 proteins with the selective autophagy related protein WDFY3 was observed. Additionally, wild‐type SOD1 and mutant SOD1 proteins were released directly to the extracellular culture media from microglia.

Conclusions: Our results provide in vitro evidence for degradation of mutant SOD1 protein by selective autophagy, which could have a protective effect on microglia during the pathological processes of ALS.

P2‐80

Neuropathological investigation of the nucleus accumbens focusing on clinical heterogeneity in Huntington disease

Mitsuaki Hirano¹; Shuji Iritani¹; Hiroshige Fujishiro¹; Youta Torii¹; Chikako Habuchi²; Hirotaka Sekiguchi³; Mari Yoshida⁴; Norio Ozaki¹

¹Department of Psychiatry, Graduate school of medicine, Nagoya University; ²Department of Psychiatry, Aichi Psychiatric Medical Center; ³Department of Psychiatry, Okehazama Hospital Fujita Mental Care Center; ⁴Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, psychiatric symptoms, and dementia. The prominent neuropathological feature is loss of neurons in the striatum, and motor symptoms are thought to correlate with the degeneration of the striatum. But the neuropathological background of psychiatric symptoms has been unknown precisely yet. The ventral part of the striatum is known as the nucleus accumbens (Acb), that is ROI as one of responsible focus of psychiatric symptoms. The purpose of the present study was to investigate the relationship between the neuronal changes in the Acb and clinical symptoms in HD.

Methods: The brains of 16 HD patients (3 behavioral/personality change onset (mean age at death/duration(years):46.0/21, HD‐P), 13 motor onset (mean age at death/duration:64.2/16, HD‐M)) and 4 control subjects (mean age at death:45.8) were investigated. Numerical cell densities for each of the large and small striatal neurons, and the ratio of small to large striatal neurons (S/L) in the Acb, caudate nucleus and putamen were determined.

Results: In HD brains, the small neuronal depopulation in the Acb was less than in the caudate and the putamen. Their neuronal depopulations were significantly greater than those of the controls (P = 0.01). There was significant increase in the large striatal neuronal number in the Acb of HD‐P compared to that of HD‐M (P = 0.04).

Conclusion: The pattern of the pathological changes of the Acb might be differed between in HD‐P and HD‐M. Some psychiatric symptoms in HD may be attributable to the degeneration of the Acb.

P2‐81

An autopsy case of malignant lymphoma associated with severe motor neuron degeneration

Tomomi Murao¹; Masahiro Higaki¹; Takako Makino¹; Yoshiro Tachiyama²; Chigusa Watanabe¹

¹Department of Neurology, National Hospital Organization Hiroshimanishi Medical Centre, Japan; ²Department of Pathology, National Hospital Organization Hiroshimanishi Medical Centre, Japan

Introduction: Extracranial malignant lymphoma was rarely reported to involve spinal motor neurons. The invasion and remote effects of lymphoma could be major causes of the conditions, but the pathomechanism is unknown. We report an autopsy case of malignant lymphoma with severe motor neuron degeneration.

Clinical summary: A 70‐year‐old male had weight loss and exertional dyspnea when he was 68. 15 months later, he began to show atrophy in the upper extrimities. 4 month after atrophy, he had dysarthria. He was hospitalized due to CO2 narcosis and underwent respirator one month after his dysarthria. Electromyogram showed active denervation potentials in all extrimities, which was consisted with Awaji criteria of ALS. Computed tomography revealed bilateral adrenal tumor. These tumors grew up rapidly, he died of insufficiency 2 months after adrenal tumor was detected and 8 months after muscle atrophy was found.

Pathological findings: Brain weight was 1370g. General pathology showed swelling of bilateral adrenal grands and dorsal roots of spinal cord. Adrenal grands had massive atypical lymphocyte infiltration, which was consisted with diffuse large B cell lymphoma (DLBCL). Neuropathologically, lymphoma cells infiltrated dorsal root ganglions and dorsal roots. There was a severe neuronal loss in the anterior horns, especially in cervical spinal cord. Lateral columns of the spinal cord were preserved. Bunina bodies was not observed. TDP‐43 positive cytoplasmic granules were revealed in the remaining motor neurons.

Conclusion: We report the DLBCL case which was clinically mimicking ALS and presented severe motor neuron degeneration with TDP‐43 positive granules.

P2‐82

Dynamic changes in microglia along with progression of lesion stages in ALSP and Nasu‐Hakola disease

Kiyomitsu Oyanagi¹; Michiaki Kinoshita²; Jun‐ichi Satoh³; Kenji Ishihara⁴; Kazuko Hasegawa⁵; Seishi Terada⁶; Mari Yashida⁷; Haruhiko Akiyama⁸; Yoshio Mitsuyama⁹; Shu‐ichi Ikeda¹⁰

¹Brain Research Laboratory, Hatsuishi Hospital; ²Department of Neurology, Suwa Red Cross Hospital; ³Department of Bioinfomatics and Molecular Neuropathology, Meiji Pharmaceutical University; ⁴Department of Neurology, Asahi Neurology Rehabilitation Hospital; ⁵Department of Neurology, Sagamihara National Hospital; ⁶Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; ⁷Institute for Medical Science of Aging, Aichi Medical University; ⁸Tokyo Metropolitan Institute of Medical Science; ⁹Department of Neurology, Daigo Hospital; ¹⁰Intractable Disease Care Center, Shinshu University Hospital

Introduction: Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), formerly hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), and Nasu‐Hakola disease (N‐HD) are neurodegenerative diseases involving brain white matter and showing axonal spheroids. Both diseases are considered to be caused by dysfunction of microglia induced by different genetic defects.

Methods: The brains of Japanese ten patients with ALSP and eight patients with N‐HD and five age‐matched controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets.

Results: In ALSP, four lesion stages based on the degree of axon loss were discerned by the authors. Stage I, patchy axon loss in the cerebral white matter without atrophy to Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. In N‐HD, similar stages were elucidated, but the internal capsule and pontine base were relatively well preserved in the N‐HD, even at Stage IV. In microglial cells, the shape, density and immunopositivity for CD68, CD163 or CD204 were changed along with the progression of the stages in both diseases.

Conclusion: The shape, density and subsets of microglia change dynamically along with the stages in the brain lesion in both diseases, and microglial changes precedes loss of axons in ALSP.

P2‐83

Familial amyotrophic lateral sclerosis with SOD1 Leu126 Ser mutation ‐ clinical and pathological studies

Tomoyasu Matsubara¹; Yuishin Izumi^2,3; Takashi Komori⁴; Hijiri Ito²; Osamu Yokota⁵; Takashi Haraguchi⁶; Kimiko Inoue⁷; Harutoshi Fujimura⁷; Yuko Saito^1,8; Shigeo Murayama¹

¹Department of Neurology and Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo, Japan; ²Department of Neurology, Vihara Hananosato Hospital, Hiroshima, Japan; ³Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; ⁴Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ⁵Department of Psychiatry, Kinoko Espoir Hospital, Okayama, Japan; ⁶Department of Neurology, National Minami‐Okayama Medical Center, Okayama, Japan; ⁷Department of Neurology, Toneyama National Hospital, Osaka, Japan; ⁸Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

Introduction: Familial amyotrophic lateral sclerosis with L126S mutation in copper/zinc superoxide dismutase (SOD1) gene is only reported in Japan. One atypical case was presented in the literature.

Method: We clinically and pathologically studied five autopsied cases of this mutation in our brain bank network with the Brain Bank for Aging Research (BBAR) ALS protocol and pursue genotype‐ phenotype correlation.

Results: The mean age at onset and duration was 51.6 years old and 8.9 years, respectively. All the cases did not present upper motor sings and four out of five cases first experienced weakness of lower extremities. Neuropathologically, all cases showed neuronal loss of spinal anterior horn and hypoglossal, facial and trigeminal motor nuclei. Betz cells were mildly affected with occasional neuronophagia. Neuronal loss involved Clarke's column with degeneration of posterior spinocerebellar tracts and middle root zones of the posterior column. Lewy body‐like hyaline inclusions were very few and basophilic inclusions with eosinophilic fibrillary stain were observed, each corresponding immunocytochemically to the epitope of phosphorylated neurofilament and SOD1. Ultrastructurally the inclusions showed ten nanometer filaments with side arms, mixed with granulofilamentous profiles.

Conclusion: FALS with L126S mutation in SOD1 gene clinically showed slowly progressive lower motor neuron disease. Accumulation of SOD1 among neurofilamentous accumulation exhibits with unique morphology of the affected neurons.

P2‐84

Comparison between measurement results of spinal fluid biomarkers and autopsy findings

Ayako Sato¹; Terunori Sano¹; Kanako Komatsu¹; Toshio Kamijyo¹; Yuji Takahashi³; Miho Murata³; Yuichi Goto²; Sumiko Yoshida¹; Yuko Saito¹

¹Department of Clinical Laboratory, National Center of Neurology and Psychiatry; ²Medical Genome Center, National Center of Neurology and Psychiatry; ³Department of Neurology, National Center of Neurology and Psychiatry

Introduction: Cerebrospinal fluid (CSF) human tau (hTau), phosphorylated tau (pTau), and amyloid β (Aβ) are regarded as good biomarkers for Alzheimer's disease (AD). We began measuring the levels of these biomarkers in our patients in 2010, of which six have undergone autopsy. Here, we reviewed the presence of CSF biomarkers in relation to the autopsy pathological findings.

Methods: The pathological diagnosis of the included patients was as follows. Case 1 involved an 86‐year‐old man with combined AD and Dementia with Lewy bodies. Case 2 involved an 83‐year‐old female with combined myelopathy and AD. Case 3 involved a 62‐year‐old female with a 10‐year history of multiple system atrophy. Case 4 involved a 74‐year‐old female with amyotrophic lateral sclerosis. Cases 5 and 6 involved 77‐year‐old and 88‐year‐old males, respectively, with progressive supranuclear palsy.

Results: In case 1, Aβ was 334 pg/mL (standard: >500 pg/mL). In case 2, hTau was 1234 pg/mL, while pTau was 110 pg/mL (<300 pg/mL, <50 pg/mL) and Aβ was 470 pg/mL. In cases 3 and 5, Aβ was low (368 pg/mL and 415 pg/mL, respectively). In case 4, hTau was high, at 613 pg/mL. In case 6, these biomarker levels were within the reference range.

Conclusion: The presence of CSF biomarkers in all cases was consistent with pathological and clinical findings, including AD pathology, myelopathy, progression of rapid pathological conditions, and activity of daily living. Thus, comparison with autopsy findings can be used to determine the accuracy of CSF biomarkers.

P2‐85

An autopsy case of familial adult‐onset neuronal intranuclear inclusion disease (NIID), with clinical differential diagnosis mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS)

Keiko Toyooka¹; Atsushi Umemura²; Chiaki Mori¹; Misaki Yamadera¹; Tomoko Oeda²; Kimiko Inoue¹; Harutoshi Fujimura¹

¹Department of Neurology, Toneyama National Hospital; ²Clinical Research Center and Department of Neurology, Utano National Hospital

Introduction: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions (NIs) in neuronal and somatic cells. In general adult‐onset cases show dementia with leukoencephalopathy. We describe an autopsy report of NIID with repeated stroke‐like episodes.

Clinical summary: A 62‐year‐old man with intense family history of dementia and stroke or encephalitis presented with left hemispacial neglect, high fever, and left hemiparesis. 2 years later dysphagia, dysarthria and right hemiparesis occurred. 6 years later he presented with aphasia following high fever. Brain magnetic resonance imaging (MRI) showed diffuse edematous lesion of left cerebral hemisphere. He died of aspiration pneumonia at the age of 72.

Pathological findings: The brain weight was 1182g, pre‐fixed. Macroscopically multifocal linear lesions in cortico‐medullary junction, focal cortical atrophy, and softening in white matter (WM) were found. Microscopically laminar necrosis in deep layer of cortex, spongiotic change in cortico‐medullary junction, and rarefaction and spongiosis of WM were seen. NIs, positive for ubiquitin and P62, were found predominantly in glial cells, compared to neurons. Large NIs were most frequently seen in Basal nucleus of Meynert, followed by thalamus and cerebral cortex. In the center and around spongiotic foci, there was little or no reactive astrocytes, while in the nearby WM, small number of bizarre shaggy‐shaped astrocytes were observed.

Conclusion: Main lesions seemed independent from the distribution of NIs, but seemed related to the insufficient reaction of astrocytes.

P2‐86

Leukoencephalopathy with vanishing white matter: Clinicopathological characteristics of a rare adult‐onset case with a homozygous EIF2B5 mutation

Naohiko Seike^1,2; Hiroshi Shimizu¹; Koh Tanaka³; Takeshi Ikeuchi⁴; Masaharu Tanaka³; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of pathology, Brain Research Institute, Niigata University; ²Department of Neurology, Takatsuki General Hospital; ³Department of Psychiatry, Mishima Hospital; ⁴Department of Molecular Genetics, Brain Research Institute, Niigata University

Introduction: Here, we present the clinicopathological characteristics of a rare autopsy case of adult‐onset leukoencephalopathy with vanishing white matter (VWM).

Clinical summary: A 64‐year‐old Japanese female with consanguineous parents exhibited irritability after delivering her son at the age of 38 years old. Two years later, cognitive impairment and hyperreflexia became evident following a traffic accident. A brain MRI study revealed severe rarefaction of the cerebral white matter with periventricular cysts, being more conspicuous in the frontal lobe. A gene analysis disclosed a homozygous missense mutation (T182M) in EIF2B5, establishing the diagnosis of VWM (Ohtake et al., 2004). She died of colon cancer at age 64.

Pathological findings: The brain weighed 950 g. In sections, the cerebral white matter showed severe atrophy and gelatinous appearance, with marked dilation of the lateral ventricles. Histologically, marked myelin pallor and axonal loss with spheroids were evident in the cerebral white matter. Distinct glial abnormalities including the appearance of bizarre‐shaped astrocytes and foamy oligodendroglia were also a feature. Immunohistochemistry disclosed reduced expression of phosphorylated eIF2alpha in the astrocytes in the cerebral white matter and the ependymal cells lining the lateral ventricles.

Conclusion: The present result suggests that in adult‐onset VMW, presumably due to the dysfunction of eIF2B, phosphorylation of eIF2alpha and subsequent stress response are attenuated in the white matter astrocytes and ependymal cells, rendering the periventricular white matter susceptible to stress such as febrile infections and head trauma.

P2‐87

A comprehensive analysis of genetic variations and neuropathologic features of patients with PARK2

Naohiko Seike^1,4; Akio Yokoseki²; Ryoko Takeuchi¹; Akinori Miyashita³; Yasuko Toyoshima¹; Osamu Onodera²; Hitoshi Takahashi¹; Atsushi Ishikawa⁵; Takeshi Ikeuchi³; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neurology, Brain Research Institute, Niigata University; ³Department of Molecular Genetics, Brain Research Institute, Niigata University; ⁴Department of Neurology, Takatsuki General Hospital; ⁵Department of Neurology, Brain Disease Center Agano Hospital

Objective: To investigate PARK2 mutational variability and neuropathologic features of PARK2 patients.

Methods: We selected eight autopsied patients showing characteristic clinical symptoms, including juvenile parkinsonism, foot dystonia and sleep benefit. Dysesthesia of limbs was seen in 3 patients. A detailed molecular analysis using frozen samples of the cerebral cortex detected previously known and novel mutations in PARK2. We evaluated biochemical, immunohistochemical and histopathological features of the CNS tissue of these patients.

Results: Homozygous and heterozygous point mutations, p.C431F, were found in patient #1 and #2, respectively. Copy number variations were found in 7 patients. Patients #3 and #4 of a family carried the heterozygous deletion of exon 4. In patients #5, #7, #2 and #6, we found a homozygous duplication of exons 6‐7, a homozygous duplication of exons 10‐11, a heterozygous duplication of exons 2‐4, and a heterozygous duplication of exon 2, respectively. Direct sequencing mRNA of patient #6 revealed a compound heterozygous mutation: triplication of exon2 and deletion of exons 2‐3. Patient #8 harbored a compound heterozygous mutation: duplication of exons 2‐4 and deletion of exons 3‐4. Western blotting and immunohistochemistry revealed faint or no expression of PARKIN. In the substantia nigra, neuronal loss and relatively mild gliosis, accompanying the specific subfields involvement pattern, was evident. Lewy bodies were found in three patients. We found mild degeneration in the spinal dorsal root ganglia.

Interpretation: A genomic and mRNA analysis is needed to identify the precise PARK2 mutations. The patients harbored the variable mutations, but the clinicopathologic phenotype appears similar.

P2‐88

A case of idiopathic normal pressure hydrocephalus with Alzheimer’ s disease pathology, presenting good clinical outcome after ventriculo‐ peritoneal shunt

Mari Shibukawa¹; Renpei Sengoku^1,2; Shigehiko Takanashi³; Aya Tokumaru⁴; Kazutomi Kanemaru¹; Shigeo Murayama^1,2

¹Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ²The Brain Bank for Aging Resaerch, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ³Department of Neurosurgery, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ⁴Department of Diagnostic Radiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: Idiopathic normal pressure hydrocephalus (iNPH) is treatable dementia caused by impaired dynamics of cerebrospinal fluid (CSF) and subsequent ventriculomegaly. Concomitant Alzheimer’ s disease (AD) pathology is reported to show poor clinical outcome after intervention.

Case Report: An 82‐year old female, suffering from chronic cognitive decline, admitted to our hospital for a few‐ month history of rapidly progressive apathy, urinary incontinence, gait disturbance and failure of oral intake. MRI showed lesion of the white matter of Fazekas grade III with ventriculomegaly, mimicking Binswanger disease. After lumbar puncture, the symptoms definitely improved. The level of Aβ 42, tau, and phosphorylated tau in CSF were consistent with AD. PIB amyloid PET was also positive. We treated her with ventriculo‐ peritoneal shunt and sampled small pieces of cerebral cortex and white matter. After shunting, the patient’ s symptoms improved dramatically until now for two years. The white matter change and dilatation of the ventricles improved after the surgery.

Neuropathology: The sampled neocortex showed senile plaques of CERAD B level and the presence of definite neurofibrillary tangles, supporting Braak AT8 stage V. The white matter presented moderate diffuse astrogliosis alone.

Discussion and Conclusion: The MRI of this case can be classified into Binswanger type without DESH. This case may suggest that improved CSF dynamics override concomitant AD pathology at least two years and improved her quality of life.

P2‐89

Neuropathological findings of an autopsy patient with sporadic idiopathic basal ganglia calcification

Yuichi Hayashi¹; Yasushi Iwasaki²; Naoko Harada¹; Megumi Yamada¹; Hisaka Kurita³; Masatoshi Inden³; Takashi Inuzuka¹; Takayoshi Shimohata¹; Mari Yoshida²; Isao Hozumi³

¹Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine; ²Department of Neuropathology, Institution of Medical Science of Aging, Aichi Medical University; ³Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University

Introduction: Idiopathic basal ganglia calcification (IBGC) is a rare and intractable disease. We report a pathologically confirmed patient with sporadic IBGC.

Clinical summary: An 83‐year‐old woman showed progressive personal change, and memory disturbance in the last 5 years. On admission, neurological examination showed akinetic mutism with no focal signs. Laboratory examination showed no abnormalities such as the serum level of Pi, Ca, and parathyroid hormone. Brain CT revealed frontotemporal atrophy and symmetric calcification in the bilateral basal ganglia, dentate nuclei, and white matter. SPECT showed decreasing regional cerebral blood flow in bilateral frontotemporal cortices. Three months later, she died due to pneumonia. Genetic analysis showed no mutation in the SLC20A2, PDGFB, PDGFRB, or XPR1 gene.

Pathological findings: The brain weight at autopsy was 1,050g. Mild frontotemporal atrophy was recognized. Microscopic analysis revealed calcification in the bilateral putamen, striatum, dentate nuclei, and cerebral and cerebellar white matters. Senile changes were also shown as Braak stage II of neurofibrillary tangles (not diffuse), stage II of AT8 stained tau, and CERAD A or Braak A of senile plaque without argyrophilic grain, tufted astrocyte or astrocytic plaque.

Conclusion: Although clinical findings of this patient were fulfilled with a probable item of diagnostic criteria for diffuse neurofibrillary tangles with calcification (DNTC), we made the diagnosis of sporadic IBGC using pathological analysis. The final diagnosis of this condition should be confirmed by the pathological findings.

P2‐90

Can we differentiate neuronal intranuclear inclusion disease from fragile X‐associated tremor/ataxia syndrome?

Aki Murayama; Keizo Sugaya; Yasuyuki Takai; Kazuhito Miyamoto; Takashi komori; Eiji Isozaki

Neurology, Tokyo Metropolitan Neurological Hospital

Introduction: Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurodegenerative disorder in the FMR1 premutation carrier. Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by the presence of eosinophilic nuclear inclusions (Nis) in the nervous system and visceral organs. We present for the first time the close similarities of clinical, neuroradiological and histopathological findings between FXTAS and NIID.

Clinical summary: A 79‐year‐old man with FXTAS showed the characteristic features of NIID and striking similarities of MRI and skin biopsy findings between the patient and a case of NIID without the FMR1 premutation. They share key diagnostic features for each disease (FXTAS: high‐intensity signal in the middle cerebellar peduncles on T2‐weighted imaging, NIID: high‐intensity signal along the corticomedullary junction on diffusion‐weighted imaging, NIs in skin biopsy). We reviewed the clinical features of FXTAS and NIID, and found that almost all of the clinical manifestations and MRI findings of FXTAS were reported in patients with NIID.

Pathological findings: Ultrastructural and immunohistochemical study of biopsied skin samples from these patients revealed NIs in the sweat gland cells, adipocytes and fibroblast. The NIs found in both disorders are indistinguishable morphologically, and share immunohistochemical features.

Conclusion: Even in the patient who satisfied diagnostic criteria for a definite FXTAS, it is possible to consider an incidental occurrence of NIID in the FMR1 premutation carrier. It is still undetermined whether the characteristic features of NIID are actually specific to NIID or also found in patients with FXTAS. Therefore, at present, we cannot differentiate NIID from FXTAS.

P2‐91

The Brains for Dementia Research cohort

Paul Francis

Wolfson Centre for Age‐Related Diseases

Introduction: Brains for Dementia Research (BDR) was funded in April 2008 and is a programme of planned brain donation which provides high quality post‐mortem brain tissue and clinical data from both those with and without memory impairment to researchers working in the field of dementia with the aim of finding new treatments and a cure for dementia. BDR comprises a network of 6 leading dementia research centres based at the Universities of Kings College London, Oxford, Bristol, Newcastle, Manchester and Cardiff and builds on established brain banks in the first 5 named.

Methods: Between 2009 and January 2018, 3,276 volunteers gave informed consent for brain donation and a total of 9,804 assessments have been completed to date. Assessments include collection of sociodemographic, cognitive and behavioural data. Following death, a full neuropathological report is produced including Braak tangle staging, Braak Lewy body score, Thal amyloid phase and CERAD stages. VCING probability is available for the majority of cases.

Results: Brains and associated data from over 600 deceased participants are available for researchers as is the assessment data on all participants. A total of 156 participants died with no cognitive impairment, 30 with MCI and over 400 with dementia with a median number of assessments per participant of 2. Within the living cohort, 72% have no cognitive impairment and further 9% MCI.

Conclusion: BDR represents a valuable cohort supporting worldwide dementia research.

P2‐92

Fukushimura Brain Bank ; Unique activity of Japanese private geriatric hospital

Hiroyasu Akatsu^1,2; Norihiro Ogawa²; Takeshi Kanesaka²; Chie Taniguchi²; Sakon Yamamoto²; Takayuki Yamamoto²; Masaki Takao³; Shigeo Murayama⁴; Yoshio Hashizume²

¹Department of Community‐Based Medical Education, Nagoya City University, Graduate School of Medical Sciences; ²Institute of Neuropathology, Fukushimura Hospital; ³Department of Neurology, Saitama International Medical Center, Saitama Medical University; ⁴The Brain Bank for Aging Researcah, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: The Fukushimura Brain Bank (FBB) was established under the auspices of the Fukushimura Hospital (FH), managed completely within the private sector. We have several buildings for the aged and disabled, and about 800 elderly people reside in the area. The FH was established in 1982 and is managed by the Sawarabi Medical Cooperative. It currently has 487 beds. Our patients mainly have dementia and cerebrovascular problems. The hospital plays a pivotal role within the village and acts as the central facility.

Methods: FBB was established in 1990. We have a long record of collecting samples from patients. This allows us as medical doctors and researchers to obtain clinical information or blood samples, sometimes even before the onset of illness. In our institute, all clinical and pathological data are held in the office of individual data management.

Results: Although our bank has gone unrecognized in the past, our farsighted efforts have been gaining considerable attention in recent years in Japan. We now have over 20 collaborators and supply more than 30 research institutes with our samples. In 2017, we have25 cases autopsies and delivered 12 institutes.

Conclusions: Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants and we became a member of the Comprehensive Brain Science Network in 2010. From 2016, we are receiving support from Platform of Supporting Cohort Study and Biospecimens Analysis Grant.

P2‐93

Standardization of frozen tissue resource‐ efforts at the National Center for Neuropathy and Neurology (NCNP) in Japan Brain Bank Net (JBBN)

Yoko Tanaka¹; Yoshiyuki Umeto¹; Kanako Komatsu¹; Terunori Sano¹; Yuko Saito¹; Shigeo Murayama²

¹Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry; ²Departments of Neurology and Neuropathology and Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: Japan Brain Bank Net (JBBN) is AMED (Japan Agency of Medical Research and Development)‐ funded national consortium to accumulate postmortem brain resource. As the PI of JBBN, we propose the standard protocol of the resource built in NCNP.

Methods: We modified the BBAR (the Brain Bank for Aging Research) protocol (www.mci.gr.jp/BrainBank/). At autopsy, recovered brains are weighed, taken pictures, separated at junction of midbrain and ponsand sagittally divided into half. More affected side of the brain with in vivo digital neuroimage is fixed in 20% buffered formalin fro 7‐ 13 days and prepared for morphological studies.Otherwise, fixed or frozen half is determined randomly. From the frozen half are obtained 7 mm thick consecutive coronal sections of the cerebrum, 5 mm thick saggital sections of the cerebellum and 5 mm thick axial sections of the brain stem. After taking photos, small pieces of representative anatomical areas are fixed in 4% paraformaldehyde two overnight and served for morphological studies. The remaining tissues are rapidly frozen on plates of dry ice, covered by powdered dry ice.The frozen tissue is sealed in Zip‐Lock® bags and stored at ‐80°.

Results: JBBN employs RIN (RNA Integrity Number) for quality control and our method is comprabale to other members. This method may be preferable to sandiwich method of dry ice plate, which will put pressure on soft unfixed brains.

P2‐94

BRAIN UK: accessing NHS tissue archives for neuroscience research

Clare Mitchell¹; Tabitha Bloom¹; David Hilton²; James AR Nicoll^1,3

¹Clinical Neurosciences, Clinical & Experimental Sciences, University of Southampton, Southampton, UK; ²Neuropathology, Derriford Hospital, Plymouth, UK; ³Department of Cellular Pathology, University Hospital Southampton, Southampton, UK

Introduction: Human tissue can be difficult for neuroscience researchers to access, with legal and ethical considerations challenging and time consuming. Prospectively collecting tissue for a study is expensive and may take many years, whereas Neuropathology archives in the UK National Health Service (NHS) contain a wealth of tissue collected over 40 to 50 years of diagnostic surgical and autopsy practice. About 500,000 cases, with 18,500 added annually, include tumour, muscle and nerve biopsies and diverse CNS disorders.

Methods: UK Neuropathologists, supported by the British Neuropathological Society, funded by the Medical Research Council and Brain Tumour Research, collaborate to form a national virtual brain bank. A linked‐anonymised database includes diagnosis and simple demographics. BRAIN UK acts as a matchmaker and its generic ethical approval covers most projects via a straightforward application process (www.brain‐uk.org).

Results: BRAIN UK reduces the time for researchers to achieve ethical approval and provides tissue via its network. 104 studies have been supported with almost 7,000 cases approved for release, resulting in 34 publications to date. Studies encompassed a wide variety of conditions including head injury, epilepsy, genetic and developmental disorders, psychiatric disorders, neuroinflammation and neurodegenerative disease. 40 tumour studies have been supported, providing large numbers of cases or rare tumour types, particularly highlighting the success of this approach.

Conclusion: BRAIN UK is a national virtual brain bank, facilitating access to under‐utilised neuropathology archives to international researchers. Tissue that would otherwise be unused has supported valuable neuroscience research.

P2‐95

Neuronal expression of Toll like receptor 3 and its correlation with microglial activation and interferon gamma expression in human rabies

Bishan Dass Radotra; Parimal Aggarwal; Rakesh Kumar Vasishta

Department of Histopathology, Postgraduate Institute of medical Education & Research, Chandigarh, India

Introduction: Rabies encephalitis is a significant health issue in Southeast Asia. Immune responses in human rabies are poorly understood. We earlier demonstrated a positive correlation between proinflammatory cytokines expression and degree of inflammation but not with rabies viral antigen load in brains of human rabies. However, the mechanisms that differentiate rabies infection into encephalitic form and paralytic form remain undetermined.

Methods: A retrospective study on 11 encephalitic and 7 paralytic post‐mortem cases of human rabies was done. Extensive sampling from different regions of brain was performed and sections from hippocampus, pons and cervical spinal cord were subjected to immunohistochemistry using antibodies against rabies viral antigen, CD68, Toll like receptor 3 (TLR3) and Interferon gamma.

Results: The inflammatory response was most marked in medulla, pons, spinal cord and hippocampus, especially in paralytic rabies cases. There was marked CD 68 positive microglial proliferation in all cases of paralytic rabies but it was seen in only 2 out of 11 cases of encephalitic rabies. Compared to diffuse cytoplasmic neuronal expression of TLR3 in paralytic rabies, the encephalitic form demonstrated perinuclear endosome like pattern. The intensity of IFN gamma expression was increased in paralytic rabies versus encephalitic rabies and it directly correlated with severity of CD68 positive microglial proliferation.

Conclusions: The perinuclear pattern may indicate relocalization of TLR3 in endosomes and inclusion bodies, which may represent an evasive strategy of rabies virus. The sub‐cellular localization of other TLRs will further shed light on immunopathogenesis and virus dissemination.

P2‐96

Preliminary findings of the pathogenesis of central nervous system granulomatous inflammation in tuberculous meningitis in South Africa: a post‐mortem immunohistochemistry study

Stefan Dan Zaharie^1,2,4; Sabine Leonore van Elsland^3,4; Martijn van der Kuip⁴; Mariana Kruger³; Marceline van Furth⁴

¹Neuropathology Unit Department of Anatomical Pathology University of Stellenbosch and NHLS South Africa; ²Department of Anatomoical Pathology, Stellenbosch University, South Africa; ³Department of Paedriatics and Child Health, Tygerberg Children's Hospital Stellenbosch University South Africa; ⁴Department of Paedriatic Infectious Diseases VUmc, Amsterdam the Netherlands

Introduction: Human post‐mortem histopathological studies in tuberculous meningitis are lacking. The cellular composition and cytokine profile of granulomas in human neuro‐tuberculosis have not yet been explored.

Methods: This retrospective study included patients diagnosed with central nervous system tuberculosis between 1975 and 2012 at Tygerberg hospital, South Africa. Histopathological assessment (Haematoxilin and Eosin, Ziehl‐Neelsen and Reticulin staining), immuno‐histochemical techniques for cellular composition (innate and adaptive immune system) and cytokine profile of brain tuberculous granulomas were performed. These findings were correlated with the brain imaging.

Results: Eighty‐three patients (40 <14 years, 43 ≥14 years of age) had a post mortem autopsy or brain biopsy performed. A total of 452 brain specimens were included. Three different types of granulomas were identified histologically and radiologically respectively: non‐necrotizing (retic positive; T2WI iso‐intense to the brain and uniform enhancement), necrotizing gummatous (retic positive; T2WI hypo‐intense with ring‐enhancement) and necrotizing abscess (retic negative; T2WI hyper‐intense with ring‐enhancement). Granulomas were perivascular located, mainly in the leptomeninges and superficial cortex. CD4 T‐helper cells were absent in post‐mortem specimens while present in biopsies. CD20 B‐cells were present in lymphoid aggregates in the leptomeninges near the pia mater. Caspase‐3 positive cells were not identified in these specimens.

Conclusions: The absence of CD4 T‐helper cells and the presence of CD20 B‐cells demonstrates the important role of the humoral adaptive immune response in tuberculous meningitis, whereas tuberculosis is a disease classically driven by a cellular adaptive immune response. Apoptosis does not seem to play a role in cell death in tuberculous meningitis.

P2‐97

A neuropathological and neurobiological study of brain malformations observed in fetuses infected by the Zika virus

Aurelie Beaufrere¹; Bettina Bessieres¹; Maryse Bonniere¹; Couderc Therese^2,3,4; Marc Lecuit^2,3,4; Laurent Nguyen⁵; Yves Ville⁶; Marianne Leruez‐Ville⁷; Ferechte Encha‐Razavi¹

¹Embryofetopathology Unit, Hopital Universitaire Necker‐Enfants Malades, APHP, Paris, France; ²Institut Pasteur, Biology of Infection Unit, Paris, France; ³Inserm U1117, Paris, France; ⁴Centre Infectiologie Necker‐Pasteur; ⁵GIGA‐Neurosciences, Liege University, Liege, Belgique; ⁶Service de Gynecologie‐Obstetrique, Hopital Universitaire Necker‐Enfants Malades, APHP, Paris, France; ⁷Laboratoire de Virologie, Hopital Universitaire Necker Enfants Malades, APHP, Paris, France

Introduction: Zika virus (ZIKV) fetopathy is associated to a high rate of congenital microcephaly with poor outcome. Our aim is to account a neuropathological description of brain anomalies in ZIKV fetopathy and to go further in the explanation of their pathogeny.

Methods: Full fetal, neuropathological, neurobiological and placental analysis was performed in three fetuses after pregnancy termination between 22‐25 weeks gestation for fetal ZIKV infection with brain malformation in accordance to French legislation.

Results: All cases displayed severe neuronal deficit and damaged cells in association with characteristic lesions of meningoencephalitis. Neurobiological study performed on the supratentorial levels found abundant ZIKV particles and an excess of progenitor cells death with endoplasmic reticulum damages. Visceral and placental examinations showed no major changes, except for testicular inflammatory changes in male fetuses.

Conclusion: Our study highlights the elective neurotropism of ZIKV. Interestingly, it permits us to identify a cascade of developmental defects associating a diffuse neuronal depletion due to an excess of progenitor cells damages to a severe brain atrophy resulting from a meningoencephalitis marked by diffuse vascular impairments.

P2‐98

PrPres deposition in the retina of sporadic, familial and iatrogenic Creutzfeldt‐Jakob diseases

Masaki Takao^1,2; Hiroaki Kimura²; Mitsutoshi Tano²; Ban Mihara²

¹Saitama International Medical Center, Saitama Medical University; ²Mihara Memorial Hospital

Introduction: The purpose of this study is to analyze PrPres deposits of the retina.

Methods: We analyzed the following cases in this study: 9 cases of SCJD (MM1), 2 cases of SCD (MM1+2), 1 case of SCJD (MM2), 3 cases of familial CJD (two of V180I and one of M232R), and 1 case of iatrogenic CJD (cadaveric dura mater graft). 5 control cases such as no neurological disease, Alzheimer disease, amyotrophic lateral sclerosis and multiple system atrophy were also used. For immunohistochemical studies to detect PrPres, monoclonal antibodies specific to prion protein 3F4 (109‐112) and 12F10 (144‐152) were used. The retinal sections were processed using a Ventana Discovery automated immunostainer.

Results: In all CJD cases, 3F4 and 12F10 immunereactive deposits (‐irs) were consistently and clearly observed in the outer and inner plexiform layers (OPL and IPL) of the retina. PrPres‐irs were coarse granular and fine synaptic patterns in the OPL and IPL, respectively. In some instances, fine granular PrPres‐irs were seen in the inner and outer nuclear layers as well as in the nerve fiber layer. No PrPres‐irs were present in the retina of control cases.

Conclusion: PrPres‐irs of the retina were consistently observed regardless of CJD cases. In addition to OPL and IPL, PrPres‐irs may be widely observed in other layers of the retina.

P2‐99

Autophagy markers in dystrophic neurites in human and experimental prion diseases

Beata Sikorska; Pawel P. Liberski

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland

Dystrophic neurites (DNs) are abnormal neuronal processes characterized microscopically by aberrant sprouting, dystrophic expansion, and accumulation of various cellular organelles and cytoskeletal and signalling proteins. In human neurodegenerative diseases DNs are often located in the vicinity of amyloid plaques. However in experimental scrapie they are observed in the neuropil regardless of the absence of amyloid plaques. Despite decades of research, the mechanism underlying the development of DNs remains unclear. We performed electron microscopy, immunohistochemistry and confocal laser microscopy in brain specimens of hamsters infected with 139A scrapie strain as well as in post mortem human brains with prion diseases. Electron microscopy showed accumulation of autophagic vacuoles as well as autophagolysosomes in dystrophic neurites in human and experimental prion diseases. Confocal laser microscopy showed immunoexpression of p62 (SQSTM1) mainly in the perikarya and to a lesser degree in the processes of the neurons. Puncta of LC3 protein were present in both the cytoplasm and processes of some neurons in the human brains. In experimental scrapie LC3 immunoexpression showed mainly fibrillary pattern. Our study indicates that autophagy is a prominent feature of dystrophic neurites and that autophagy increase in neurons may be compartment‐specific. This work was partly supported by Poland National Science Centre grant 2015/19/B/NZ4/03234

P2‐100

Difference Between the Immune Pattern of Granulomatus Injuries in the Lung and Brain During Infection With Mycobacterium Tuberculosis

Diana Villa Sepulveda¹; Citlaltepetl Salinas Lara¹; Erick Gomez Apo²; Daniel Rembao Bojorquez¹; Marco Antonio Duran Padilla²; Laura Graciela Chavez Macias²; Carlos Sanchez Garibay¹; Itzel Rocio Manzano Espinoza¹; Francisco Javier Martinez Hernandez¹; Eduardo Pablo Sanchez Martinez¹

¹National Institute of Neurology and Neurosurgery “Dr. manuel Velasco Suarez”; ²General Hospital of Mexico “Dr. Eduardo Liceaga”

Tuberculosis (Tb) is the treatable infectious disease with the highest lethality in the world. Central Nervous tuberculosis (CNS‐Tb) represent 1% of all Tb cases, and 5‐10 % of extrapulmonary tuberculosis. Is the most devastating form of Tb, with a morbi‐mortality upper of 50% and 30% of survivors develop sequels. The CNS is protected by the blood brain barrier (BBB), this confers immune privilege characteristics, hence, physiopathology studied on the periphery of the organism should not be applied to the CNS. We evaluated 16 cases with CNS‐Tb diagnose to describe, identify and contrast the histological and immunological pattern of granulomatous lesions in brains versus lungs. Histological lesions and cell types present in sections of paraffin‐embedded tissue from CNS and lung were identified; IL‐1 β IL‐4, IL‐6, TNF α e INF γ detection was realized by immunohistochemistry. The most frequent granulomatous lesions in the CNS were the diffuse cellular accumulations, without central necrosis, unlike lung granulomas, which presented a circular, well‐defined shape and central caseous necrosis. Regarding the expression of cytokines, in the CNS lesions, it was found that the positive response of the inflammatory cells was lower than in the pulmonary tissues. However, we found statistical significance in the expression of IL‐1 β IL‐6 and TNF α (p < 0.05), demonstrating that neurons actively participate in the induction and / or maintenance of the CNS immune response, a finding of great importance that will change the image of the neuron as an active participant in infections of the central nervous system

P2‐101

Pathological progression of genetic Creutzfeldt‐Jakob disease with a PrP V180I mutation

Akio Akagi^1,2,3; Yasushi Iwasaki¹; Maya Mimuro¹; Tetsuyuki Kitamoto⁴; Masahito Yamada²; Mari Yoshida¹

¹Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University; ²Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa; ³Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa; ⁴Department of Neurological Science, Tohoku University Graduate School of Medicine

Introduction: In comparison to sporadic Creutzfeld‐Jakob disease (sCJD) with MM1‐type and MM2‐cortical (MM2C)‐type, genetic CJD with a prion protein gene V180I mutation (V180I gCJD) is clinically characterized by onset at an older age, slower progress, and the absence of visual disturbances or cerebellar symptoms. In terms of pathological characteristics, gliosis and neuronal loss are generally milder in degree, and characteristic spongiform change can be observed at both the early and advanced stages. However, little is known on the progress of spongiform change over time or its mechanisms.

Methods: In this study, to elucidate the pathological course of V180I gCJD, statistical analysis of the size and dispersion of the major diameters of vacuoles in six V180I gCJD cases was performed, with five MM1‐type sCJD and MM2C‐type sCJD cases as controls.

Results: As a result, V180I gCJD showed no significant difference in vacuolar diameter regardless of disease duration. In addition, the dispersion of the major diameters of vacuoles in V180I gCJD was larger than that in the MM1‐type, which was smaller than that in the MM2C‐type.

Conclusion: We speculated that the absence of difference in the size of the vacuoles regardless of disease duration suggests that tissue rarefaction does not result from the expansion of vacuole size and increase in number of vacuoles in V180Ig CJD. These features were considered to be significant pathological findings of V180I gCJD.

P2‐102

Diverse clinical feature and neuropathological findings on Gerstmann‐Straussler‐Scheinker syndrome ‐ Seven cases report

Masafuchi Ryo

Department of Neurology Tokai University Tokyo Hospital

Background: Gerstmann‐Straussler‐Scheinker syndrome (GSS) is well known as one of the hereditary prion disease. However, GSS is one of the rare disease, while not only clinical features but also neuropathological findings are still obscure. We have a chance to examine seven cases of GSS in our hospital group. We investigated these cases and made a special reference about them.

Objective: To clarify the relationship between clinical feature and neuropathological findings of GSS.

Methods: We examined genetically confirmed each GSS cases, whose mutation cites were P 102L; five cases, P 105L; one case, and G 217A; one case. Clinical features and neuropathological findings were investigated by conventional means.

Results: Most popular point mutation of GSS was P 102L in Japan. Our result was same. In P 102L mutation cases, onset of age was around 50yrs, duration of illness was around 10yrs. Course of illness was slowly progressive phase about 5 years, and then, rapidly progression to apallic state for another 5 years. Initial symptoms were personality change or ataxic gait. In neuropathological examination, cerebellar degeneration, plaque were common findings, however, cerebral lesion, brainstem lesion and spinal lesion were different in case by case. Level of spongiosis was revealed slight to severe.

Conclusions: Pathological change of cerebellum and plaques were common in GSS, however, divergent clinical feature and divergent neuropathological findings in our cases.

P2‐103

Leptomeningeal inflammatory aneurysm associated with leptomeningitis by tuberculosis. Exceptional finding in a postmortem case of systemic tuberculosis

Erick Gomez‐Apo; Sebastian Coronel‐Montero; Veronica Velasco‐Vales; Luis Manola‐Aguilar; Eric Mendoza‐Oviedo; Victor Mendez‐Cano; Laura Chavez‐Macias

General Hospital Of Mexico

Background: Intracranial infectious aneurysms can be caused by bacterial, fungal, or viral organisms, the vast majority result from bacterial infections. Infectious aneurysms associated to leptomeningeal tuberculosis are very uncommon. We had an extensive review of literature and we found reported six cases.

Clinic Case: A twenty‐eight‐year‐old man with medical history of annal abscess since one month before. The final event started two months before death with headache, agitation and unconsciousness; he entered to Hospital. At physical exploration, he had Glasgow 7/15, painful stimulation was present and decreased muscular strength. CT reported cerebral edema. Neurosurgery service realized a ventriculostomy and started antifimic treatment. He continued with neurologic deterioration and death.

Autopsy Findings: We found systemic tuberculosis with miliar affection pattern in lungs, diaphragm, liver and spleen. The annal abscess was resolved. There was an extensive leptomeningeal tuberculosis and a thalamic tuberculoma. On microscopy, there was an extensive meningovasculitis, arterior cerebral arteries were merged, and anterior cerebral artery had wall inflammation, elastic layer was ruptured and lumen was dilatated due to infectious pseudoaneurysm. We detected acid‐alcohol‐resistant bacilli with Ziehl‐Neelsen stain.

Conclusions: In our experience, we had 24 autopsy cases of leptomeningeal tuberculosis in 2000‐2017 period; but we think than the evidence of pseudoaneurysm due to tuberculosis is exceptional; furthermore, only six cases of tuberculous pseudoanerysm were informed in central nervous system.

P2‐104

18F‐THK5351 PET findings in familial Creutzfeldt‐Jakob disease with V180I mutation: a clinicopathological study

Tomotaka Shiraishi¹; Renpei Sengoku^1,2; Yasuhiro Sakashita²; Yasushi Nishina¹; Kazutomi Kanemaru¹; Aya Tokumaru³; Kenji Ishii⁴; Yuko Saito⁵; Shigeo Murayama^1,2

¹Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ²Department of Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geritaric Hospital and Institute of Gerontology; ³Department of Radiology, Tokyo Metropolitan Geritaric Hospital and Institute of Gerontology; ⁴Research Team for Neuroimaging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ⁵Department of Pathology and Laboratory Medicine, National Center of Neurology and Psychiatry Hospital

Introduction: THK5351 originally developed as tau tracer but our study of frozen brains confirmed binding to monoamine oxidase B, which is highly expressed in astroglia. Thus, THK5351 can be a good tracer to detect astrogliosis.

Clinical summary: An 86‐year‐old Japanese woman presented with progressive insomnia and apathy for several months. Parkinsonism, cerebellar signs, and myoclonus were absent in entire clinical course. MRI showed hyperintensity of the cerebral cortex on diffusion‐weighted images (DWI) and swelling in the cerebral cortex on T2‐weighted images. Cerebrospinal fluid showed positive cut off value for tau and 14‐3‐3 protein, and RT‐ QUIC of prion protein (PrP) was positive. Analysis of PrP gene revealed V180I mutation with methionine/valine heterozygosity at codon 129. THK5351 PET images disclosed intense radioligand uptake in subcortical white matter regions, corresponding to DWI high signals. She died of hepatoma four months after the PET scan.

Pathological findings: Neuropathological examination showed extensive spongiformic changes with various‐sized and non‐confluent vacuoles in the cerebral neocortex. Neuronal loss is mild and immunostaining with 3F4 demonstrated very weak synaptic‐type PrP deposition in the cerebral cortex. Western blot analysis of protease‐resistant PrP showed a characteristic pattern with V180I CJD. The area of high uptake of THK5351 corresponded to astrogliosis without depiction of tau.

Conclusion: This case confirmed that THK5351 could decorate astrogliosis and be employed to detect neurodegeneration, irrespective of tauopathy.

P2‐105

First autopsy proven case of VPSPr: Variably protease‐sensitive prionopathy in Japan

Kazuko Hasegawa¹; Saori Oonuma¹; Kanako Komatsu²; Yuko Saito²; Saburo Yagishita¹; Tetsuyuki Kitamoto³

¹Department of Neurology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan; ²Department of Neuropathology, NCNP, Kodaira, Japan; ³Division of Neurological Science, Tohoku University school of medicine, Sendai, Japan

Introduction: Variably protease‐sensitive prionopathy: VPSPr is a newly described human prion disease in the spectrum of Creutzfeldt‐Jakob disease: CJD in 2008. In UK and USA cohort study in 2013, only 5 cases of VPSPr have been identified (prospectively and retrospectively) in UK, indicating VPSPr as a rare phenotype. Biochemical investigation characterizes that VPSPr shows detectable protease‐sensitive fragments. Some investigators reported that molecular overlaps can be found between usual protease‐resistant prionopathy and VPSPr in sporadic CJD.

Clinical summary: 81 y‐o women admitted to our hospital asked from GP, because of her memory disorder, rt‐sided dysesthesia, and high intensity ribbon‐like appearance in some cortices in DWI. At that time, she had several test: MMSE: 23 points, FAB: 6/30 points, CSF‐QUIC: negative, PSD on EEG: negative. Six months later, she hanged around and admitted into care center, but still she could eat. She died of pneumonia after 3.5 years from disease onset. Pathological findings and immunoblot for anti‐prion protein: Brain weight: 1186g, Macroscopic findings: Generally mild atrophy, but severe in the temporal pole.

Histological findings: Neuronal loss and vacuolation were diffusely detected in the cerebral cortex and the basal ganglia with anti‐prion antibody immunostaining (3F4). Mild neurofibrillary tangles, senile plaques and grains were also detected in the cerebral cortices. In immunoblot, variably protease‐sensitivity was detected as VPSPr.

Conclusion: The first case of sporadic CJD is reported as autopsy and immunochemical detected VPSPr in Japan.

P2‐106

An autopsy case of progressive multifocal leukoencephalopathy associated with idiopathic CD4 positive lymphocytopenia with a ten‐year clinical course

Tatsuya Fukumoto^1,2; Ryoko Takeuchi¹; Fumiaki Katada¹; Susumu Sato¹; Hidehiro Shibayama¹; Shigeo Murayama³; Toshio Fukutake¹

¹Department of Neurology, Kameda General Hospital; ²Department of Clinical Neuroscience, Tokushima University; ³Department of Neurology and Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Introduction: Progressive multifocal leukoencephalopathy(PML) is a deadly demyelinating disease, caused by reactivation of the polyomavirus JC(JCV). PML associated with idiopathic CD4 positive lymphocytopenia(ICL) is rare and there are few reports of autopsy cases.

Clinical summary: A 54‐year‐old man presented with dysarthria and gait disturbance. His symptoms deteriorated over months and he became akinetic mutism. FLAIR image of MRI showed high signal lesions in the pons and cerebellum, which extended to the cerebral white matter. PCR of CSF for JCV was positive and he was diagnosed with PML, although biopsy was not performed. Blood analyses revealed marked decrease in CD4 positive cell count. Serological tests for HIV were negative and there was no evidence of immunodeficiency, consistent with ICL. Cytarabine wasn't effective. 10 years after the onset, he died of cholangitis and postmortem examination was performed.

Pathological findings: Severe loss of myelinated fibers was seen in the white matter of the cerebrum, brainstem and cerebellum. The white matter of the temporal lobe was partially spared. Typical findings of JCV infection were not observed, such as abnormal oligodendrocytes. Immunohistochemical analysis using anti‐VP1 antibody was negative. PCR of the frozen section and formalin‐fixed paraffin‐embedded section for JCV were both positive.

Conclusions: This is an extremely rare case of long‐term survival of PML associated with ICL. Although there was no pathological evidence, the clinical presentation and results of PCR were consistent with PML. A long period of time may affect the pathological findings. This case may indicate that histopathological remission can occur in PML.

P2‐107

An autopsy case of MM2‐Thalamic Creutzfeldt‐Jakob disease

Zen‐ichi Tanei¹; Masako Ikemura²; Munetoshi Hinata²; Ken‐ichiro Sato³; Atsushi Iwata³; Masashi Fukayama²; Shigeo Murayama¹

¹Department of Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ²Department of Pathology, Graduate School of Medicine, the University of Tokyo; ³Department of Neurology, Graduate School of Medicine, the University of Tokyo

A 39‐year‐old man admitted to the hospital with a two‐year history of fatigue and anxiety, one‐year history of insomnia, and four‐month history of cognitive deterioration, diplopia, dysarthria and difficulty in walking for loss of balance. He was disoriented and disinhibited. Neurological examination revealed hyperreflexia, horizontal gaze‐evoked nystagmus, internal strabismus and nasal voice. EEG and MRI were unremarkable. FDG‐PET scans and Tc99m‐ECD SPECT detected mild left thalamic hypometabolism. DAT‐SPECT showed symmetrical reduction in bilateral putamen. CSF biomarker study revealed mild elevation of tau, but other biomarkers were not contributory, including phosphorylated tau, Aβ, 14‐3‐3 protein and RT‐QUIC of prion protein. There was no response to donepezil, levodopa or steroid pulse therapy. The patient presented with progressive deterioration of mental state into akinetic mutism for a few months. At age 41, he died of respiratory arrest. Neuropathological examination revealed severe neuronal loss and gliosis in thalamus and inferior olivary nucleus, accompanying secondary tract degeneration, while other areas were relatibvely preserved. SNP at codon 129 of prion gene was Met/Met and western blot analysis detected faint band of type 2 prion protein. Neuropahological diagnosis was MM2T (thalamic form)‐ CJD. This case is unique in relatively young onset and secondary degeneration involving thalamic efferent fibers in addition to inferior cerebellar peduncle.

P2‐108

Clinical courses of patients with Creutfeldt‐Jakob disease in Shizuoka Institute of Epilepsy and Neurological Disorders, Japan

Tomokazu Obi¹; Takashi Matudaira¹; Yasukiyo Araki¹; Kinya Yamazaki¹; Akira Sugiura¹; Tatsuhiro Terada¹; Yuta Nakano²; Tetsuyuki Kitamoto²; Shigeo Murayama³

¹Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders; ²Department of Neurological Science, Tohoku University Graduate School of Medicine; ³Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital

Background & Objective: From 2002, we have diagnosed and cared forty‐six Creuzfeldt‐Jakob disease (CJD) patients in Shizuoka Institute of Epilepsy and Neurological Disorders (SIEND).

Methods: 46 CJD patients presenting sequentially to SIEND between November 2003 and April 2018 were studied.

Results: All patients were clinically diagnosed as probable CJD based on prion disease medical treatment guidelines in Japan. Initial symptoms were gait disturbance 13, speech disturbance 6, apathy 6, visual disturbance 4, limb palsy 4, agraphia 2, geographical disorientation 2, dizziness 2, involuntary movement 2 and others 5. Onsets were usually acute (25) or subacute (8), but 12 patients abruptly developed neurological symptomes within one day. Mean age of onset was 69.0 years old. Sex was male 19 and female 27. Mean disease duration from onset to death was 86 weeks. Sporadic CJD patients were 33 cases. Genetic CJD patients were 13 cases including eleven E200K and two V180I. 38 CJD patients were cared, and eventually 35 patients died in SIEND. Autopsy was performed in 14 patients. 13 neuropathological findings showed definite diagnosis of CJD. We reported CJD patients having specific neuropathological findings and clinical utility of brain SPECT.

Conclusion: We reviewed 33 probable and 13 definite CJD patients. Abrupt onsets were frequently reported from family members. E200K mutations were very common in Genetic CJD patients. It is important to diagnose correctly and care CJD patients in central Shizuoka, Japan.

P2‐109

Panencephalopathic creutzfeldt‐jakob disease with severe small vessel disease

Jose M. Bonnin¹; Francine Epperson¹; Rose Marie Richardson¹; Eugene C. Lai²; Brendan Lee³; Lindsay Burrage³; Jill A. Mokry³; Paolo Moretti⁴; Bernardino Ghetti¹

¹Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN; ²Department of Neurology and Neuroscience, Houston Methodist Hospital, Houston, TX; ³Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; ⁴Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT

A 47‐year‐old male presented with progressive cognitive impairment, severe dysarthria, involuntary movements, urinary incontinence, and inability to ambulate without assistance. Two years ealier, he noted intermittent episodes of dizziness, imbalance, lightheadedness, and visual disturbances as well as rapid weight loss. Subsequently, he developed ataxia and dysarthria. On examination, he was alert, followed simple commands, but had severe dysarthria. His MoCA was 18/30. Extensive serological studies revealed no metabolic abnormalities, toxins, heavy metals, or infectious diseases. A paraneoplastic panel was unremarkable and genetic studies (complete ataxia panel, Fragile X) were negative. The cerebrospinal fluid revealed elevated protein, reduced A/T index (Aβ42/t‐Tau), normal p‐Tau, and negative 14‐3‐3 protein. A whole‐body PET revealed no abnormalities and a head MRI showed mild white matter signal abnormalities. Diffuse but non‐specific cerebral dysfunction was documented on EEG.

He died 5 years after the onset of symptoms. Neuropathological examination revealed marked brain atrophy and severe ventricular enlargement. The atrophy was particularly severe in the cerebral cortex, with almost complete loss of nerve cells, and severe astrogliosis. In the centrum semiovale, the axonal and myelin loss was severe. The basal ganglia, thalamus, amygdala, were markedly atrophic. Hippocampal atrophy was less prominent.There was also severe arteriolosclerosis. Immunoreactivity to PrP, with a synaptic pattern, was prominent in the cerebral and cerebellar cortices. The white matter degeneration in panencephalopathic Creutzfeldt‐Jakob disease is generally considered to be secondary to the neuronal loss and the relatively long clinical course. A possible role of an associated severe small vessel disease has been rarely evaluated.

P2‐110

Coexistence of PrP and tau amyloids associated with the PRNP Q160X nonsense mutation

Bernardino Ghetti¹; Jose Bonnin¹; Holly Garringer¹; Rose Richardson¹; Francine Epperson¹; Jamie Fong²; Julio Rojas²; Andrea Legati³; Anna Karydas²; Giovanni Coppola³; Michael Geschwind²

¹Indiana University; ²University of California San Francisco; ³University of California Los Angeles

Cognitive and behavioral changes, similar to those seen in Alzheimer disease (AD) may be associated with nonsense (stop codon) mutations in PRNP. A 31‐ year‐old male was diagnosed as having an orbitofrontal syndrome, peripheral neuropathy, and a gastrointestinal disorder. Individuals in three generations of the family had suffered from presenile dementia. The patient's condition deteriorated rapidly and he died at 33 years of age. An autopsy limited to the CNS was carried out. The brain weighed 1,055 grams. Atrophy was severe in the frontal and temporal lobes, amygdala, hippocampus, corpus callosum, and the hemispheric white matter. The occipital horns of the lateral ventricles were severely enlarged. Histologic preparations with Luxol Fast Blue/Hematoxylin & Eosin revealed eosinophilic deposits in the cerebral and cerebellar parenchyma, often associated with the vasculature. For immunohistochemical analysis, antibodies to prion protein (PrP), tau, GFAP, alpha‐synuclein, AIF1/IBA1, and calbindin were used. Cerebral and cerebellar cortices, subcortical nuclei, spinal cord, and the pos‐ terior nerve roots contained PrP‐immunoreactive plaques as well as extensive deposits in the vessel walls. Thioflavin S highlighted the PrP deposits. The PrP angiopathy involved arterioles and capillaries. With the exception of the cerebellum, there was also a severe tau pathology, that mirrored that of the PrP deposits in the cerebral cortex and basal ganglia. DNA, extracted from brain tissue, revealed the PRNP Q160X stop codon mutation, which causes deposition of amy‐ loid made of truncated PrP. The pathogenesis of tau pathology associated with truncated PrP requires further investigation.

P2‐111

Sensory nervous system involvement in a footpad‐inoculated, Japanese encephalitis mouse model

Tzeh Long Fu¹; Kien Chai Ong²; Soon Hao Tan²; Kum Thong Wong¹

¹Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ²Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Introduction: Japanese encephalitis (JE) remains the most important cause of mosquito‐borne viral encephalitis. Based on the clinical observation that there is early and severe involvement of the thalami, we hypothesize that JE virus (JEV) could use peripheral sensory nerves and sensory pathways to enter the CNS following a mosquito bite. We investigated this using a footpad‐inoculated, JE mouse model.

Methods: Groups of 2‐week‐old ICR mice were inoculated in the left hindlimb footpad with JEV (Nakayama strain; 10⁶CCID50/ml, volume 20µl). Tissues from sacrificed animals were collected on days 1 through 5 for histopathological analysis (n=6) and viral titration (n=6). Viral antigens and viral RNA were detected using specific immunohistochemistry and in situ hybridization, respectively.

Results: Viral antigens/RNA were focally detected in neurons of the thalamus contralateral to injected side (n = 4/6) at 3 days post‐infection (dpi) and in the ipsilateral posterior horn of the spinal cord at 4 dpi. Dorsal root ganglia (DRG) and peripheral nerves were also positive for viral antigens/RNA. After 3 dpi, viral antigens/RNA could also be detected in other parts of the CNS, including cerebral cortex, brainstem, cerebellum and hippocampus. Virus could be cultured from the CNS starting 3 to 4 dpi but low viremia was cleared by 5dpi.

Conclusion: Early infection of the thalamus, peripheral nerves and DRG in this mouse model suggests that JEV could use sensory nerves/pathways for neuroinvasion following introduction into the skin after a bite from an infected mosquito.

P2‐112

An orally‐infected hamster model for Coxsackievirus A16 infection confirms neurovirulence

Yuan Teng Hooi¹; Kien Chai Ong²; David Perera³; Kum Thong Wong¹

¹Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ²Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ³Institute of Health & Community Medicine, Universiti Malaysia Sarawak, Sarawak, Malaysia

Introduction: Coxsackievirus A16 (CV‐A16) is a common orally‐transmitted, enterovirus that usually causes self‐limiting, hand‐foot‐mouth disease (HFMD). Rarely, it has been reported that CV‐A16 may cause severe neurological complications but this has not been adequately shown in human studies. Neither is there a good small, orally‐infected animal model available for study. We developed a consistent, orally‐infected CV‐A16 hamster model to investigate HFMD associated with CNS infection.

Methods: Groups of 7‐day old hamsters were orally inoculated with 100 μl (dose 1.12 x 10⁵CCID50/ml) of a CV‐A16 mouse adapted virus strain, and observed for signs of infection. The tissues from infected hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively. Tissues were also obtained for viral titration.

Results: All hamsters were infected and exhibited signs of infection such as ruffled fur, limb weakness, and paralysis, and were moribund or dead by 3‐4 days‐post infection. Viral antigens/RNA were detected in squamous epithelia in the oral cavity, paw and skin, and in the CNS. Neurons in the brain stem and spinal cord were mainly infected with no apparent involvement of the cerebral cortex, hippocampus and cerebellum dentate nucleus. Viral antigens/RNA were also detected in skeletal muscles and brown fat. Positive viral culture confirmed viral replication in the CNS.

Conclusion: The findings in this unique model confirmed that CV‐A16 is neuronotropic. The distribution of squamous lesions is reminiscent of HFMD. This model is potentially useful for neuropathogenesis studies, and for anti‐viral drugs and vaccine testing.

P2‐113

A Japanese encephalitis virus quasispecies with an E gene mutation exhibits reduced neurovirulence

Shu Pin Yu¹; Kien Chai Ong²; Soon Hao Tan²; Tomohiro Ishikawa³; Kum Thong Wong¹

¹Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ²Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ³Department of Microbiology, Dokkyo Medical University School of Medicine, Tochigi, Japan

Introduction: Japanese Encephalitis virus (JEV) is the leading cause of viral encephalitis. Since viral genome mutations could potentially affect phenotype, we investigated E gene mutations in a JEV quasispecies to determine its neurovirulence.

Methods: A quasispecies (JEV‐M) purified from a clinical isolate, was sequenced and E gene mutations were found. The phenotype of JEV‐M was tested on human neuroepithelioma (SK‐N‐MC) and murine neuroblastoma (NIE‐115) cells, and in a mouse model. Infectious clones harboring these mutations were generated from a published JEV clone (Muar‐FLC), and phenotypically characterized to confirm the findings.

Results: JEV‐M showed significant reduced infectivity in SK‐N‐MC and NIE‐115 cells from 24 hour post infection (hpi) to 96 hpi. In the mouse model infected via footpad, 50%, 75% and 100% survival rates were observed in groups of animals infected with 20µL of 10⁶, 10⁵ and 10⁴ CCID50/ml of virus, respectively. Viral antigens/RNA in the cerebral cortex, hippocampus, thalamus, medulla and spinal cord were detected in the sick but not in surviving animals. The two E gene mutations (Y59H and A327T) identified in JEV‐M were successfully incorporated in infectious clones, and tested to confirm the phenotype. The Y59H mutant clone showed a similar phenotype to JEV‐M.

Conclusion: E gene mutations in the JEV genome could cause a reduction in neurovirulence both in vitro and in vivo.

P2‐114

Trophic Factors Involved In Developmental and Adult Hippocampal Neurogenesis In Humans

Homa Adle‐Biassette^1,2,3; Sara Cipriani²; Isidre Ferrer⁴; Gabor Kovacs⁵; Eleonora Aronica⁶; Philippe Manivet^2,3; Pierre Gressens²

¹Department of Pathology, Lariboisiere Hospital, Paris, France; ²PROTECT, INSERM, Universite Paris Diderot; ³Centre de Ressources Biologiques BB‐0033‐00064, Hopital Lariboisiere, Paris; ⁴Institute of Neuropathology, IDIBELL, Barcelona, Spain; ⁵Institute of Neurology, Medical University of Vienna, Austria; ⁶Department of Pathology, AMC, Amsterdam, Netherland

Introduction : We have previously described progenitor subtypes, their neurogenic potential and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus in human fetuses and healthy and alzheimer's disease adults. Here, we assessed the expression of VEGF‐A, VEGF‐C, VEGFR2, VEGFR3 and TRKB in the developing and adult human hippocampus and characterized their cellular localization. Summary: At GW13, VEGFA, VEGF‐C, VEGFR3 and TRKB were strongly expressed in radial glial cells (RGCs) of the hippocampal ventricular zone (VZ) and the dentate anlage (DA). From GW16, their expression started to decrease in RGCs of the VZ, although VEGFR3 and VEGF‐C expression increased in vessels and in the RGCs of the DA. In parallel, VEGF‐A and TRKB expression increased in pyramidal and granule neurons from GW25. The expression of VEGF‐A in neurons, vessels and glial cells persisted in adulthood. VEGFR2 was only detected in vessels. Conclusions: These observations support experimental data suggesting that VEGFR3 and VEGF‐C directly stimulate progenitors in the developing human hippocampus. We did not find evidences of the neurogenic potential of VEGFA as VEGFR2 was only detected in vessels. Supported by EU grant HEALTH‐2011‐2.2.2‐2/Develage

P2‐115

Fiber tract anomalies of the CNS: anatomical variants of the midline‐crossing mode of the anterior commissure

Akira Hori¹; Erika Hori²

¹Institute for Pathology/Neuropathology, Medizinische Hochschule Hannover; ²Institute for Pathology, Muehlenkreiskliniken Minden

Introduction: Fiber tract anomalies are a rare CNS‐malformation; some known anomalies are agenesis of corpus callosum, abnormal course of the pyramidal tract including uncrossed/partially crossed pyramidal tract, and supracallosal dorsal fiber tracts. Additionally, we have previously described an abnormal entrance of the posterior spinal nerve roots into the spinal cord, and a trapping of a small number of callosal fibers by a unilateral fornix. The latter is clinically non‐significant, therefore a normal anatomical variant. We now recorded some variable midline‐crossing modes of the anterior commissure in relation to the fornix and studied it statistically.

Methods: Macroscopic observation of 90 brains (Female:Male=34:56) in a non‐selected human autopsy series, all adults (median: 52yrs) and without any malformations.

Results: The majority of examined cases showed an anterior commissure midline crossing anterior to the fornix by 68.9% (62 cases; F:M=22:40) and posterior to the fornix by 17.8% (16 cases; F:M=6:10). 12.2% (11cases; F:M=5:6) of the cases showed that the anterior commissure crosses anterior to the fornix on one side and posterior on another side. One particular case exhibited on one side only a part of the anterior commissure fibers looping around the fornix. Clinical correlations could not be established.

Conclusion: The variable crossing mode of the anterior commissure in relation to the fornix is a normal anatomical variant.

P2‐116

Development of 3D neuropathology based on tissue clearing technique

Kazuki Tainaka; Rie Saito; Akiyoshi Kakita

Brain Research Institute, Niigata University

Optical sectioning with light‐sheet microscopy in combination with recent advances in tissue‐clearing techniques is one of the promising strategies toward three dimensional visualization of large human tissues. Recently, we have developed a rodent brain/body clearing and imaging method, termed CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis). Hydrophilic CUBIC cocktails significantly enhanced whole mouse brain clearing via effective delipidation and homogenizing mismatched RIs without signal loss from fluorescent proteins. Additionally, an aminoalcohol in CUBIC reagent displayed highly efficient decolorization of the PFA‐fixed blood by the elution of heme chromophore from hemoglobin. Our CUBIC cocktails are also applicable to human tissue block. We will introduce potential availability of CUBIC‐based 3D neuropathology.

P2‐117

Basic study on the development of simple cognition system and device of the non‐learning and non‐stress type in the Alzheimer's disease model mouse

Masahiro Ii¹; Hiroshi Kohama¹; Kosuke Yonekura¹; Yuki Kaida¹; Keiko Kato¹; Shinichiro Kitao^1,2; Masako Kato^2,3; Takashi Takeuchi^1,3; Shinsuke Kato¹

¹Division of Neuropathology, Tottori University Faculty of Medicine; ²Division of Molecular Pathology, Tottori University Faculty of Medicine; ³Department of Veterinary Laboratory Medicine, Tottori University Faculty of Agriculture

Introduction: The previous cognition system for mice is designed on the base that an individual can learn. We try to establish the simple cognition system and device for Alzheimer's disease (AD) mice that cannot have adequate cognition, being based only on daily‐living movement without invasive maneuvers.

Methods: We used Tg(APPSWE)2576KhaTg(Prnp‐MAPT*P301L)JNPL3HImc mice as AD mice and age‐matched littermates as normal controls. We set food and water box as Food Zone (FZ) at the corner in the routine breeding cage. We analyzed two conditions that there was Toy as the apparatus of behavior restrictions (Toy condition) or not (no Toy condition). Under Toy condition, we placed Toy at the opposite direction to FZ in the cage: the space (equivalent to Nesting hole Zone: NZ) was naturally formed between cage wall and Toy. We studied only on daily‐living movement without invasive maneuvers, and used modified‐Smart3.0 software for behavior analyses, using Activity factor among mouse behaviors. The analysis time was only ten minutes.

Results: Under no Toy, there was no difference between AD and normal mice. Under Toy, AD mice had significantly higher Activity in FZ (AD pattern), and reciprocally normal mice showed significantly higher Activity in NZ (Normal pattern). Neuropathologically, AD‐pattern mice exhibited senile plaques:SPs and neurofibrillary tangles:NFTs, but Normal‐pattern mice did not have SPs and NFTs. Our behavioral results corresponded to neuropathological results.

Conclusion: We have succeeded to develop the new system and device that can easily distinguish the mice having AD pathology from normal mice in only ten minutes.

P2‐118

Longitudinal diffusion tensor imaging and neuropathology revealed nerve fiber alterations in hereditary microcephaly model mice

Hiroshi Ogi¹; Nobuhiro Nitta²; So Tando¹; Akira Fujimori³; Ichio Aoki²; Shinji Fushiki⁴; Kyoko Itoh¹

¹Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine; ²Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences; ³Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences; ⁴The Center for Quality Assurance in Research and Development, Kyoto Prefectural University of Medicine

Introduction: Autosomal recessive primary microcephaly‐5 (MCPH5) is caused by the mutation of the abnormal spindle‐like, microcephaly‐associated (ASPM) gene. This study aimed to demonstrate a correlation between radiological and pathological analyses in evaluating postnatal brain development using MCPH5‐model mice.

Methods: In vivo MRI was conducted on ASPM ortholog (Aspm) knockout (KO) mice, at postnatal three weeks (P3W) and P10W. Morphological and diffusion tensor imaging (DTI) analyses were performed with MRI data. Complementary histopathological analyses of their brains were carried out at P5W and P13W.

Results: In the MRI analysis, KO mice showed significantly smaller brain sizes and larger ventricles at P3W and P10W. DTI analysis revealed that the fractional anisotropy (FA) values in the KO mice were significantly lower than those in the control mice in both the cortex and white matter, at P3W and P10W. Developmental changes in the FA values from P3W to P10W were less remarkable in the KO mice especially in the cortex. In the neuropathological analysis, the ratios of the horizontal to the vertical neurites (horizontal ratio) were significantly higher in the cortex, with a remarkable increase according to maturation at P13W in the control mice. Transient decrease in myelin basic protein‐positive ratio in the white matter was observed in the KO mice at P5W.

Conclusion: Temporal FA changes were correlated with pathological findings such as abnormal neurite outgrowth, assessed by the horizontal ratio, which may be applicable for analyzing diseased human brain development.

P2‐119

Expression of transporters of glucose and fructose in epithelial cells of the choroid plexus and ependymal cells of human and mouse brains

Yoichi Chiba¹; Koichi Matsumoto¹; Ryuta Murakami¹; Naoya Uemura^1,2; Masato Mashima^1,3; Ken Yanase^1,2; Ryuji Fujihara¹; Machi Kawauchi¹; Masaki Ueno¹

¹Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University; ²Department of Anesthesiology, Faculty of Medicine, Kagawa University; ³Department of Perinatology and Gynecology, Faculty of Medicine, Kagawa University

Introduction: Incidence of obesity and type 2 diabetes mellitus is increasing in parallel with an increase in dietary fructose intake, and recent studies suggest that these conditions are associated with cognitive decline and dementia. To clarify the molecular basis of the relationship between high sugar intake and brain dysfunction, we investigated the localization of glucose and fructose transporters in human and mouse brains.

Methods: Human brain samples (n = 6) were obtained at autopsy from 3 patients without and 3 patients with neurological diseases. Expression of GLUT5, GLUT8, and SGLT2 were examined with immunohistochemistry. The study was approved by the institutional ethics committee of the Faculty of Medicine, Kagawa University. Brain tissues were obtained from 9‐ to 10‐week‐old male C3H/He mice for immunohistochemistry, immunoblotting, and RT‐PCR.

Results: Immunoreactivity of fructose transporters, GLUT5 and GLUT8, were observed in epithelial cells of the choroid plexus and ependymal cells. Immunoreactivity of GLUT8 were also observed in subependymal astrocytes and microglia. Immunoreactivity of SGLT2, a sodium glucose co‐transporter mainly expressed on the apical side of epithelial cells of the renal proximal tubules, was detected in choroid plexus epithelial cells.

Conclusion: These results suggest that choroid plexus epithelial cells have direct transport systems for fructose and glucose, through which intravascular fructose and glucose move into cerebrospinal fluid. These molecules may have some roles in the pathogenesis of cognitive decline and dementia in patients with metabolic syndrome.

P2‐120

Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis

Reiji Hommyo¹; Satoshi O Suzuki¹; Nona Abolhassani²; Hideomi Hamasaki¹; Masahiro Shijo¹; Norihisa Maeda¹; Hiroyuki Honda¹; Yusaku Nakabeppu²; Toru Iwaki¹

¹Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University; ²Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University

Introduction: Down‐regulation of μ‐crystallin (CRYM) in the hippocampi of patients with Alzheimer's disease was revealed by microarray analyses of autopsied brains from the Japanese general population (the Hisayama study). CRYM reportedly has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur‐containing cyclic ketimines. We examined the expression pattern of CRYM in the rat brain during development. As CRYM is reportedly expressed in the corticospinal tract (CST), we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS).

Methods: CRYM expression in developing rat brains was examined by immunohistochemistry and immunoblotting. CRYM expression in human ALS brains was examined by immunohistochemistry.

Results: In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and CST in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. In these regions, CRYM‐positive and negative neurons were distributed in a mosaic pattern. In human ALS brains, we observed marked loss of CRYM in the CST, especially distally.

Conclusion: CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and later performs cell‐specific functions in selected neuronal populations. The expression patterns of CRYM may reflect interactions with T3 or ketimines. The results also indicate that CRYM can be used as a marker of axonal degeneration in the CST.

P2‐121

Rapid immunohistochemical staining using an electric stirring device is useful for intraoperative brain tumor diagnosis

Katsushi Taomoto¹; Hideyuki Ohnishi¹; Yoshihiro Kuga¹; Yuji Kodama¹; Yasuko Hirayama¹; Takanori Hirose²

¹Department of Neurosurgery,Ohnishi Neurological Center; ²Department of Diagnostic Pathology, Hyogo Cancer Center

Introduction: Intraoperative diagnosis of brain tumors is crucial for the decision of surgical procedures and application of intraoperative chemotherapy. Recently, an electric stirring device for rapid immunohistochemical staining (R‐IHC) has been developed and its application to the intraoperative diagnosis is highly expected. In the present study, we examined the utility of R‐IHC using the device for intraoperative brain tumor diagnosis.

Materials and methods: Frozen sections of 211 cases of brain tumor were used for R‐IHC with the electric stirring device, Hist Tech® R‐IHC®(Nakayama Co. Ltd.). The primary antibodies used were EMA, somatostatin receptor 2, S‐100 protein, GFAP, IDH1 R132H, p53, cytokeratins, TTF‐1, lymphoid markers, and Ki‐67.

Results: The mean time from receiving materials to getting results of R‐ICH was about 30 minutes. The mean number of stains for each case was five. Most antibodies gave reliable results, but Ki‐67 labeling on frozen sections was less than that on formalin‐fixed paraffin‐embedded (FFPE) sections. In particular, R‐IHC was effective in the following tumor types: 1) the diagnosis and grading of infiltrating glioma, 2) the diagnosis of metastatic tumor and the speculation of the primary site, 3) the diagnosis of malignant lymphoma, and 4) the diagnosis of meningioma, schwannoma, and pituitary adenoma.

Conclusion: In the present study, we confirmed the usefulness of R‐IHC using electric stirring device, which gave satisfactory stainings mostly within acceptable short periods. It should, however, be kept in mind that some antibodies, such as Ki‐67 may be less sensitive on frozen sections than FFPE sections.

P2‐122

Characterization of the seed Aβ oligomers in the brains of APP transgenic mice

Mayu Hakozaki‐Kashiwagi^1,2; Yasushi Naka¹; Tomoya Tajiri¹; Masashi Fukayama²; Tadafumi Hashimoto¹; Takeshi Iwatsubo¹

¹Department of Neuropathology, Graduate School of Medicine, the University of Tokyo; ²Department of Pathology, Graduate School of Medicine, the University of Tokyo

Introduction: Extracellular deposition of amyloid‐β (Aβ) peptides is crucial to the pathogenesis of Alzheimer's disease (AD), in which the critical role of the seeding capacity of aggregated forms of Aβ has been implicated. It has been shown that intracerebral injection of brain‐derived Aβ fractions can exogenously induce Aβ deposition in Aβ precursor protein (APP) transgenic (tg) mice, although the molecular characteristics of the Aβ species that act as seeds in vivo remains elusive.

Methods: The Tris‐soluble fractions of the brains of APP tg mice were separated by size‐exclusion chromatography using a Superdex 75 column, and the Aβ‐positive peaks verified by ELISA were injected into the unilateral hippocampus of the 10‐month‐old APP tg mice. Four months later, the Aβ in the hippocampus of the injected side was examined by Aβ immunohistochemistry and compared with those in the contralateral side. Fractions of wild‐type mice were examined as a control.

Results: Tris‐soluble Aβ in the brains of APP tg mice were separated into three peaks at elution positions of >200 kDa, 50‐60 kDa and 10‐20 kDa. Intrahippocampal injection of the >200 kDa Aβ fraction induced a unique pattern of Aβ deposition within the specific layers and fiber tracts of the hippocampus, whereas the 50‐60 kDa Aβ, as well as the >200 kDa fraction from the wild‐type mice did not elicit of Aβ.

Conclusions: The high‐molecular‐weight soluble Aβ oligomers of >200 kDa derived from Aβ‐laden brains represent the seed Aβ species that play critical roles in the propagation of Aβ pathology, possibly through conformational changes.

P2‐123

Development of bipolar charged hydrogel for neuronal tissue engineering

Satoshi Tanikawa¹; Shingo Semba¹; Lei Wang^1,2; Mishie Tanino¹; Yusuke Ishida¹; Hirokazu Sugino¹; Jun Suzuka¹; Masumi Tsuda¹; Shinya Tanaka^1,2

¹Department of Cancer Pathology, Faculty of Medicine, Hokkaido University; ²Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI‐CoRE), Hokkaido University

Introduction: Central nervous system has limited regenerative capacity. Current treatment strategies for traumatic brain injury, stroke or neurodegenerative diseases are insufficient to recover the function. Tissue engineering, replacing tissue with cells and artificial scaffold, is expected to neuronal regeneration. Cell adhesion to scaffold is one of the most important factors for anchorage‐dependent growth including neural cells. Surface charge and wettability on substrates are important factors that affect cell adhesion and differentiation. We present that bipolar charged polymer hydrogel serves as scaffold for maintenance and differentiation of neural stem cells (NSCs).

Materials and Methods: Copolymer hydrogels composed of anionic AMPS monomer with sulfonic and cationic APTMA with trimethyammonium residue was prepared at different ratios (anion to cation ratios were 1 to 0, 5 to 1, 3 to 1, 1 to 1 and 1 to 3). NSCs were cultivated on these gels and evaluated cell adhesion and differentiation marker by real‐time PCR and Western blotting.

Results: NSCs efficiently attached to neutral and hydrophilic gel designated as P(AMPS‐co‐APTMA)‐S1A1. NSCs survived and extended cell body on this gel. Furthermore, P(AMPS‐co‐APTMA)‐S1A1 gel promoted to astrocytic differentiation of NSCs through Jak/Stat pathway and suppressed oligodendroglial differentiation through decreasing Olig2 expression.

Conclusion: P(AMPS‐co‐APTMA)‐S1A1 hydrogel has a potential to provide scaffold for maintenance of NSCs with differentiation to astrocytic cell lineage which may contribute to protect neuronal cells and repair the brain tissue.

P2‐124

The development of the prominent immunohistochemistry method for human cholinergic neurons

Satoru Morimoto¹; Mieko Harada¹; Yasumasa Kokubo²; Shigeo Murayama¹

¹Department of Neuropathology and Brain Bank for Aging Research (BBAR), Tokyo Metropolitan Institute of Gerontology (TMIG), Tokyo, Japan; ²Kii ALS/PDC Research Center, Mie University Graduate School of Regional Innovation Studies, Mie, Japan

Introduction: Cholinergic neurons as lower motor neurons, pedunculopontine nucleus (PPN), and nucleus basalis of Meynert (NBM) are so important for neurophysiology and neurodegenerative diseases as Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). However, there are no immunohistochemistry method for human cholinergic neurons that can withstand neuropathological evaluation. Therefore, we developed a new immunohistochemistry method for human cholinergic neurons.

Methods: We adopted anti‐ChAT (mouse IgG1, AMAb91129; CL3169) for a specific antibody, Target Retrieval Solution, Citrate pH 6 (Dako)/autoclaving for pretreatment, and Can Get Signal immunostain ® (TOYOBO) for a sensitizer in immunohistochemistry process. As sites to stain, we chose human sliced specimens including each spinal cord, PPN, and NBM of controls and patients with PD, ALS and amyotrophic lateral sclerosis/parkinsonism‐dementia complex (Kii ALS/PDC).

Results: We succeeded to stain human cholinergic neurons clearly with excellent signal to noise ratio in all investigated sites. Moreover, we confirmed the accumulation of phosphorylated α‐synuclein in PPN of a patient with PD, and the loss of lower motor neurons in spinal cord of patients with Kii ALS/PDC by using this method.

Conclusion: Our method is useful for neuropathological diagnosis and researches of neurodegenerative disorders.

P2‐125

The Future of ICDNS

Manuel B Graeber

Brain and Mind Centre, University of Sydney, Sydney, Australia

Knowledge wants to be free! This realization formed the starting point of an initiative that culminated in the submission of an article on the International Classification of Diseases of the Nervous System (ICDNS), which I organised in 2002 (1). Jim Lowe and I also launched a website, www.icdns.org, and a follow‐up article in PLoS Medicine (2) was complemented by a letter from Richard Stallman (3), with whom I had corresponded about the ‘free community’ approach. Unfortunately, the ICDNS project got delayed. All spare time during my later London years was absorbed by an arguably even more important project on the ethics of human brain banking (4). It further became clear that the online format originally chosen for ICDNS was suboptimal. In addition, the original idea had been to do most work anonymously but named authorship is more motivating and name recognition also creates trust. Now that concepts have matured and technology has advanced, I would like to undertake a fresh effort to make ICDNS useful for the international community of neuropathologists. The idea has remained that open debate and democratic consensus can eliminate the limitations of closed‐circle classifications. The revised format of an online text(book) that can be used freely for training purposes seems most promising. I am also and especially inviting colleagues from countries where our medical specialty still needs to be established, including Australasia, South America and Africa to get in touch via email (webmaster@icdns.org) or, more effective, community chat (https://icdns.ngrok.io). 1.LancetNeurology2002;1(6):340; 2.PLoSMedicine2004;1(2):e16; 3. PLoSMedicine2005;2(2):e47; 4.http://blogs.plos.org/speakingofmedicine/2011/12/21/ensuring‐respect‐for‐the‐donated‐brains‐of‐children/

P2‐126

D‐neuron pathology: New clue for neuropsychiatric research

Keiko Ikemoto

Department of Psychiatry, Iwaki Kyoritsu General Hospital

Introduction: Relationship between pathophysiology of mental disorders and trace amines, such as beta‐phenylethylamine, or tyramine has long been described from early in 1970's. D‐neuron (trace amine neuron) system was discribed by Jeager et al. in 1983 in rat central nervous system. The author specified human D‐neuron system, and examined D‐neuron neuropathology of neuropsychiatric illnesses to discover novel treatments.

Methods: Immunohistochemistry by using antibodies against monoamine‐synthesizing enzymes and postmortem brains of controls, patients with schizophrenia obtained by legal and pathological autopsy (registered cases of national hospital research resource network) were used. Available references were used to establish pathophysiological hypothesis.

Results: I specified anatomical subgroups of mammalian D‐neurons into 18 groups from D1 (spinal cord) to D18 (cerebral cortices) in a caudorostral order. D‐neurons could not be detected in monkey striatum, whereas, D‐neuron system was developed in human forebrain. In postmortem brains of patients with schizophrenia, D‐neurons were reduced in D15 and D16 (Ikemoto et al., 2003). Newly established “D‐cell hypothesis of schizophrenia” (Ikemoto, 2012, 2016), a pivotal theory to link neural stem cell dysfunction hypothesis to dopamine hypothesis, explained mesolimbic hyperdopaminergea and disease progression of schizophrenia (Kippin et al., 2005), showing a novel direction in medicinal chemistry, trace amine‐associated receptor 1 (TAAR1) as a target receptor (Revel et al., 2013). Domestically developed SEP‐363856, a TAAR1 partial agonist, was preceded to a phase 2 clinical trial in foreign countries.

Conclusion: D‐neuron pathology induces neuropsychiatric novel therapeutic strategies. The D‐neuron might be available in future regenerative medicine using induced pluripotent stem cells (iPSC).

P2‐127

Maternal repeated cold stress alters morphology of noradrenergic neurons of offsprings: Immunohistochemical study using rat model

Keiko Ikemoto

Department of Psychiatry, Iwaki Kyoritsu General Hospital

It is important to know whether prenatal environment influence on the morphology of offspring central nervous system. Here the author shows the findings of an immunohistochemical study by using prenatal stress model of rats. The author and her colleagues examined the effect of maternal repeated cold stress (RCS) on the development of catecholamine neurons in offspring using 8‐day‐old offspring and tyrosine hydroxylase (TH) immunohistochemistry. RCS was loaded to pregnant rats between days 10 and 20 after fertilization. The frontal and cingulate cortices tended to contain fewer TH‐immunoreactive (‐ir) fibers, and the density of TH‐ir varicosities with a large size (more than 7 μm in diameter) was significantly (p<0.05) less in rats prenatally exposed to RCS than controls. The locus coeruleus neurons of rat prenatally exposed to RCS displayed less TH immunoreactivity than controls. In the medullary C1/A1 catecholaminergic field, size of TH‐ir neurons was smaller and the quantity of TH‐ir fibers was less in prenatally exposed rats, although the difference was not significant. In the originating and projection fields of midbrain dopaminergic systems, we could not detect any differences in TH‐ir structures between the two groups. These findings showed that prenatal RCS impaired development of catecholaminergic neurons, notably noradrenergic neurons of pups. The result is concordant with our clinical observations showing the efficacy of noradrenergic stimulants for patients with developmental disorders including attention deficit hyperactivity disorder (ADHD).

P2‐128

Differential Gene Expression Analysis in Pediatric Langerhans Cell Histiocytosis, A Comparison between CNS and Bone Lesions

Francia Victoria Abarcar De Los Reyes

Pathology Laboratory UERM Memorial Medical Center

Introduction: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with well‐documented CNS and bone involvement. However, the underlying mechanisms that causes the lesion to be selectively expressed primarily as a CNS lesion or as a bone lesion has not been clearly elucidated. This study compared the difference between the upregulated and downregulated genes in the LCH of the brain versus the bone samples of pediatric patients to determine the difference in the gene expression.

Methodology: Gene frequency counts from the whole exome sequence data of pediatric patients with LCH were analyzed. The frequency of expression were differentiated by analysis of the transcript reads to determine if there is a change in the upregulated and downregulated transcripts in the CNS LCH versus the bone LCH group.

Results: CNS LCH patients exhibited an upregulation in the Dysbindin Domain Containing 1 (DBNDD1) gene versus matched controls that showed a downregulation of the said gene. In comparison, B Cell Associated Protein (BCAP29) and Pyruvate Dehydrogenase Kinase (PDK2) was upregulated in the CNS cases but was not expressed in the normal brain control. Oxysterol Binding Protein Like 7 (OSBPL7) is increased in both the brain and bone LCH cases but was not expressed in the normal brain control.

Conclusion: Identification of unique gene expression in CNS versus bone LCH contributes to the understanding of the underlying mechanisms that may explain the difference in tumor behavior in different locations.

Symposium 16 (Collaboration with JSDR): S16‐1

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program 1988‐2018

Thomas G. Beach

Banner Sun Health Research Institute, Sun City, Arizona, USA

The Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) is a longitudinal clinicopathological study focused on normal aging, Alzheimer's disease and Parkinson's disease. Autopsies are performed as part of the Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute has been in operation for 30 years, with more than 1,900 autopsies performed (brainandbodydonationprogram.org). Autopsies and tissue banking were limited to the brain until 2005 but since then more than 630 whole‐body donations have been received. Most Program subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. The median age at death is 83, with 376 that died over age 90 and 27 that were centenarians. Subjects receive standardized general medical, neurological, behavioral, neuropsychological and movement disorders assessments annually during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3 hour median postmortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 3100 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 500 investigators located in 38 US states and 23 countries.

S16‐2

The Netherlands Brain Bank

Inge Huitinga¹; Mignon de Goeij¹; Michiel Kooreman¹; Ling Shan¹; Minke Groot¹; Petra Brom¹; Laura Boekel¹; Roxanne Roshandel¹; Cassandra van Tuijn¹; Mark Mizee¹; Adelia Adelia¹; Isabell Ehmer¹; Afra van den Berg¹; Paul Evers¹; Nina Fransen¹; Annemieke Rozemuller²

¹Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands; ²Amsterdam University Medical Centre, Amsterdam, The Netherlands

The Netherlands Brain Bank (NBB) is a professional brain bank with extensive prospective donor programs that provides brain tissue from donors with neurological and psychiatric diseases and non‐diseased controls on an open access basis for research worldwide. Annually, the NBB performs 120‐160 autopsies with impressive short post mortem delays (mean 6.5 h) of donors that gave informed consent for the use of their brain and clinical files for research, in some cases supplemented with post mortem MRI. Since its start in 1985, the NBB has provided tissue from more than 4300 autopsies of donors with neurological and psychiatric diseases and controls to 700 research projects all over the world, resulting in more than 1700 scientific publications. Currently, the NBB has over 4800 registered donors. As partner of BrainNet Europe, a European consortium of brain banks, the NBB drafted an ethical Code of Conduct for Brain Banking. The sources for this Code of Conduct were laws, regulations and guidelines (Declarations, Conventions, Recommendations, Guidelines and Directives) issued by international key organizations, such as the United Nations, Council of Europe, European Commission, World Medical Association and World Health Organization. The Code of Conduct addresses fundamental topics, such as the rights of the persons donating their tissue, the obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality, protection of personal data, collections of human biological material and their management, and transparency and accountability within the organization of a brain bank. The Code of Conduct was ratified by all European brain banks in 2009.

S16‐3

To establish all‐ Japan Brain Bank Network

Yuko Saito^1,2,3

¹National Center of Neurology and Psychiatry Brain Bank; ²Japanese Brain Bank Net (JBBN); ³Japanese Brain Bank Network for Neuroscience Research (JBBNNR)

National Center of Neurology and Psychiatry (NCNP) is based on Ministry of Health, Labor and Welfare, Japan and its mission is for cure of intractable neurological and psychiatry disorders. For this mission, NCNP has been trying to establish all‐ Japan brain bank network. NCNP established Research Resource Network of National Hospital Organization in 1997, followed by the brain bank network with brain donation program of Parkinson disease in 2006, expanding to intractable neurological disorders in 2014 and then, in‐ house psychiatric disorders in 2017. In collaboration with NCNP, the Brain Bank for Aging Research (BBAR), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology is playing a promoting role of brain banking in Japan and a core of the Japanese Brain Bank Network of Neuroscience Research funded by Ministry of Education, Culture, Sports, Science and Technology, Japan. The Psychiatric Bank of Fukushima Prefecture Hospital is recruiting brain donors of psychiatric disorders nationwide. In 2016, Japan Agency for Medical Research and Development funded Japanese Brain Bank Net as NCNP Brain Bank as the core, focused on psychiatric disorders as well neurological disorders. All brain bank representatives in Japan are members of the Brain Bank Committee, the Japanese Society of Neuropathology, which was established in 1986 and cultivate the consensus of detailed neuropathological studies. We are now trying to develop our system to NPO‐ PO collaboration level as in U.S. and U.K. This symposium will be the starting point. the Japanese Brain Bank Net: NCNP, Brain Research Institute, Niigata University; Aging Medical Institute, Aichi Medical University; Department of Psychiatry, Nagoya University; Department of Psychiatry, Okayama University; Tokyo Metropolitan Matsuzawa Hospital; Psychiatric Brain Bank, Fukushima Prefectural University (PBBF); BBAR the Japanese Brain Bank Network of Neuroscience Research: BBAR, NCNP, Mihara Institute of Cardiovascular Disorders Brain Bank, Fukushimura Brain Bank, PBBF.

S16‐4

Limitations of routine immunopathologic diagnoses in neurodegenerative diseases of the aging brain: implementing the added value of brain/biobanking (frozen‐brain biochemistry, genetics, CSF, blood, other biofluids)

Colin Louis Masters

The Florey Institute, The University of Melbourne

The time is fast approaching when the standard morphological approach to neuropathologic diagnoses is no longer adequate. In unravelling the comorbidities of the aging brain, the diagnostic attributions of Alzheimer's disease (AD), small and large vessel vascular disease, diffuse Lewy body (DLB) disease, hippocampal sclerosis (HS) and the frontotemporal dementias (FTD) require a greater precision than can be achieved by morphologic examination alone.

The clinician who brings to the autopsy table the results of a full clinical history (including family history and neuropsychometrics on cognition and behavior), neuroimaging (3T MRI), molecular PET imaging (Aβ, tau, α‐synuclein, and markers of synaptic integrity such as synaptophysin, neurogranin, SNAP‐25, NfL etc.), plasma/serum biomarkers of neurodegeneration and vascular disease, and somatic and germline DNA sequences, must work hand‐in‐glove (so to speak) with the neuropathologist, who in addition to the routine morphometric approach to Aβ tau, α‐synuclein, TDP‐43, and other determinants of neurodegenerative processes, will facilitate the quantitative estimation of these molecular entities from post‐mortem frozen brain samples.

The technologies to achieve this holistic approach are now available. The challenge lies in implementation.

Symposium 17: S17‐1

Response assessment of bevacizumab for glioblastoma: Comparison between PET and pathological studies

Keisuke Miyake¹; Daisuke Ogawa¹; Masaki Okada¹; Tetsuhiro Hatakeyama¹; Reiji Haba²; Takashi Tamiya¹

¹Department of Neurological Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan; ²Department of Diagnostic Pathology, Kagawa University Faculty of Medicine, Kagawa, Japan

Introduction: MRI is the morphological imaging modality; however, it creates confusion about the efficacy of bevacizumab therapy. PET uses radiotracers to attain metabolic and molecular imaging; especially ¹¹C‐methionine (MET) and ¹⁸F‐fluoromisonidazole (FMISO) PET possibly provide precise evaluation of bevacizumab therapy. This study aims to assess MET and FMISO PET studies to evaluate pathological examinations induced by bevacizumab therapy for glioblastoma.

Methods: Between July 2013 and December 2017, seven patients with glioblastoma were treated by resection after bevacizumab therapy (biweekly with bevacizumab; dose, 10 mg/kg). Based on the MET and FMISO accumulation, tumor specimens were resected and assessed for VEGF and HIF‐1 α expression levels. MET with a tumor‐to‐normal (T/N) ratio cut‐off of >3 and the FMISO with a tumor‐to‐blood (T/B) ratio cut‐off of >1.6 were associated with metabolically active tumor cells. Furthermore, we assessed sensitivities and positive predictive values (PPVs) for the evaluation of the presence of tumor and the accumulation of PET studies.

Results: MET accumulation correlated with the presence of a tumor (sensitivity, 88.5%; PPV, 50%; p =0.022). FMISO accumulation correlated with the presence of a tumor (sensitivity, 91.9%; PPV, 73.9%; p<0.001). Pathological studies revealed that high expression of VEGF and HIF‐1 α were observed in tumors with high accumulation of MET and FMISO. Nonactive tumor was detected in regions with low FMISO T/B ratio.

Conclusions: Assumedly, high accumulation regions of MET and FMISO correlate with resistance to bevacizumab therapy, and MET and FMISO could be potential biomarkers for the assessment of pathological examination of glioblastoma during bevacizumab therapy.

S17‐2

Definition of pathological total removal of glioblastoma multiforme

Shoko Yamada¹; Akira Matsuno²

¹Department of Neurosurgery, Teikyo University Hospital Mizonokuchi, Kawasaki, Japan; ²Department of Neurosrugery, Teikyo University Hospital, Tokyo, Japan

Background: Glioblastoma multiforme (GBM) recurs within one year after microscopic total removal of the tumor. This suggests that microscopic total removal of GBM is totally different from pathological total removal.

Methods:

1. Expression of CD15 or CD133, which are stem cell markers, was investigated in cultured rat GBM C6 cells.

2. In GBM patients, expression of CD15 or CD133 was examined in the tumor tissue and in the normal brain tissue of 1cm and 2cm away from the pathological tumor border.

Results: No CD133 positive C6 cells were identified; however, a CD15‐positive cell was confirmed 3 days after initiating cell culture. Ratio of CD15‐positive cells to negative cells was constant during culturing, and this ratio was also constant even after temozolomide treatment. In 6 human GBM cases, CD15 or a CD133‐positive cells were identified in 1cm away from the tumor border in one case, 1.5cm in two cases, and 2cm in three cases.

Conclusions: Based on the C6 cell culture study, it is obvious that some mature GBM cells can differentiate to precursor cells. This result also suggests that precursor cells have already existed when GBM is diagnosed on MRI. The precursor cells are identified not only in tumor tissue but also in the histologically normal brain tissue of 2cm away from a tumor border. Therefore, to reach to the pathological total removal of GBM, normal brain tissue of 2cm away from a tumor border should be resected.

S17‐3

Immune checkpoint molecules in high‐grade gliomas in adults

Eiichi Ishikawa; Masahide Matsuda; Shingo Takano; Akira Matsumura

Departments of Neurosurgery, Faculty of Medicine, University of Tsukuba

Programmed cell death 1(PD‐1) and its ligand, PD ligand‐1 (PD‐L1) are representative molecules of various immune checkpoint molecules, which are attracting attention in high‐grade gliomas (HGGs). Here we review recent literatures including our papers regarding expression of PD‐1/PD‐L1 and other immune checkpoint molecules in HGGs. Glioblastoma (GBM) showed significantly stronger expression of PD‐L1 compared to lower‐grade gliomas. Moreover, PD‐L1 expression was different among GBM subgroups (for example, increased expression of PD‐L1 in mesenchymal tumor samples). Association between PD‐L1 expressions and outcome of GBM patients is debatable. In our study, which investigated PD‐1 expression in GBM specimen pairs at the initial stage and recurrent stage after RT plus TMZ therapy at our institute, an increase in the number of PD‐1‐positive cells in the latter specimens was associated with worse outcome after recurrence. Theoretically, tumor vaccine therapies induce up‐regulation of immune checkpoint molecules in tumor tissues, which may also be a mechanism of this vaccine failure especially in the recurrent phase. Thus, expression of the immune checkpoint molecules including PD‐L1 depend on grading and subtypes of gliomas and affected by treatment for glioma patients.

S17‐4

Persistent restoration of the immunosuppressive tumor microenvironment in glioblastoma by bevacizumab

Ryota Tamura¹; Toshihide Tanaka³; Keisuke Miyake⁴; Kentaro Ohara²; Yukina Morimoto¹; Ryuichi Kanai⁶; Ryuichi Kanai⁵; Takashi Tamiya⁴; Kazunari Yoshida¹; Hikaru Sasaki¹

¹Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan; ²Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan; ³Department of Neurosurgery, Jikei University Kashiwa Hospital, Chiba, Japan; ⁴Department of Neurosurgery, Kagawa University Hospital, Kagawa, Japan; ⁵Department of Neurosurgery, Jikei University Hospital, Tokyo, Japan; ⁶Department of Neurosurgery, Eiju General Hospital, Tokyo, Japan

Background: Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated.

Methods: The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of PD‐1/PD‐L1, CD3, CD8, Foxp3, CD163, and CD11b was analyzed by immunohistochemistry.

Results: The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naive Bev group. PD‐1+ T cells significantly decreased in the effective or refractory Bev group compared with the naive Bev group. The number of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naive Bev group. Both Foxp3+ Tregs and CD163+ TAMs significantly decreased in the effective or refractory Bev group compared with the naive Bev group. CD11b+ myeloid cell infiltration was decreased in the effective Bev group compared with the nave Bev group. These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors.

Conclusions: Bev restores the immunosuppressive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy.

S17‐5

Clinical experience of symptomatic epilepsy in patients with high grade gliomas

Toshio Hirohata¹; Kenichi Oyama¹; Yuko Sasajima²; Fukuo kondo²; Akira Matsuno²

¹Department of Neurosurgery, Teikyo University School of Medicine, Tokyo, Japan; ²Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan

Background: Brain tumor‐related epilepsy (BTRE) has a tendency to appear in low‐grade tumors more frequently than high‐grade tumors in their clinical courses. Here, we report clinical cases of BTRE complicated with high‐grade gliomas, and treated with combination therapy of antiepileptic drugs.

Case 1: A 68‐yo male suffered status epilepticus initially, and a right frontal tumor was pointed out. Levetiracetam (1,000mg/day) was administered, and perampanel (4mg/day) was added after the second seizure. The tumor was resected surgically, and diagnosed as anaplastic oligodendroglioma, grade 3.

Case 2: A 39‐yo female suffered a generalized epileptic seizure initially, resulting in diagnosis of anaplastic astrocytoma of her left frontal lobe. Valproic acid (600mg/day) and zonisamide (300mg/day) were administered. Eight years later, an epileptic seizure took place again, and recurrence of left frontal tumor was pointed out. Perampanel (4mg/day) was added. The tumor was diagnosed as secondary glioblastoma multiforme, grade 4, after the second surgery.

Case 3: A 68‐yo female suffered status epilepticus initially, and treated with levetiracetam (2,000mg/day) for the diagnosis of symptomatic epilepsy caused by right frontal encephalitis. Ten months later, a right frontal tumor was pointed out, triggered by recurrent epileptic seizures. Perampanel (4mg/day) was added. The tumor was resected surgically, and diagnosed as glioblastoma multiforme, grade 4.

Discussion: BTRE in the present three cases of high grade gliomas were controlled successfully by the combination therapy with perampanel, which is a selective AMPA‐type glutamate receptor antagonist, and other representative drugs of presynaptic sodium channel or calcium channel inhibitors and GABA receptor agonists.

S17‐6

Vessel mimicry as a target of antiangiogenic therapy for glioblastoma

Shingo Takano¹; Eiichi Ishikawa¹; Masahide Matsuda¹; Narushi Sugii¹; Takao Tsurubuchi¹; Noriaki Sakamoto²; Hiroyoshi Akutsu¹; Akira Matsumura¹

¹Department of Neurosurgery, Faculty of Medicine, University of Tsukuba; ²Departmeny of Pathology, Faculuty of Medicine, University of Tsukuba

Purposes: Vessel mimicry is an important target of resistance to anti‐angiogenic therapy for solid tumors. In this study, the frequency and the treatment of vessel mimicry with glioblastoma were investigated.

Methods: 14 cases of glioblastoma sections were double‐stained immunofluorescently with type IV collagen and CD34. The number of vessel mimicry (collagen+ / CD34‐ tubular structure) was counted and the frequency was calculated from total vessel number. Chetomin, a HIF‐1 α inhibitor, was applied for U87 glioblastoma mimicry model in vitro and in vivo intracerebral model.

Results: Vessel mimicry was observed in all cases and 4.2% (range 2.0‐5.7%) of tumor vessels. Chetomin (10nM) strongly inhibited U87 vessel mimicry in vitro (13.7% under normoxia and 33.3% under hypoxia). U87 intracerebral tumor size 28 days after implantation was similar with /without chetomin administration. Vessel density and vessel mimicry was under investigation.

Conclusion: Vessel mimicry was observed in 4.2% of glioblastoma vessels. Chetomin inhibited glioma vessel mimicry in vitro, but not inhibited tumor growth in vivo in the brain. Vessel mimicry is a treatment target of anti‐angiogenic therapy of glioblastoma.

Special Lecture 4: SL4

Molecular Mechanisms of Glioma Progression and Therapy Resistance

Guido Reifenberger

Institute of Neuropathology, Heinrich Heine University Duesseldorf

Malignant gliomas are the most common primary intrinsic brain tumors. Despite aggressive multimodal therapy, including neurosurgical tumor resection, radiotherapy and chemotherapy with DNA‐alkylating drugs such as temozolomide, malignant gliomas invariably progress and recur after first‐line therapy. The present lecture will provide an overview of molecular mechanisms driving malignant progression, development of therapy resistance and tumor recurrence of malignant gliomas, in particular the most common type of IDH‐wildtype glioblastoms. A particular focus will be placed on investigations of the genetic evolution of glioblastomas prior to and following treatment by large‐scale molecular profiling of pairs of primary and recurrent tumors from individual patients using next generation sequencing of tumor genomes and transcriptomes. In addition, our ongoing studies on the role of non‐coding RNAs, including microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), in glioma progression and therapy resistance will be presented. These studies cover molecular profiling of primary glioma tissue samples as well as functional analyses of selected lncRNA candidates using transient and stable knock‐down glioma models, which are being characterized by cell biological assays, RNA sequencing and proteomics, In addition, the roles of candidate lncRNAs on glioma sensitivity to radiotherapy and temozolomide chemotherapy were determined in vitro and in orthotopic mouse models. These approaches identified and functionally characterized novel genetic and lncRNA‐mediated pathomechanism that may contribute to clonal evolution and resistance to cytotoxic therapy of malignant gliomas.

Symposium 18: S18‐1

The ligand dependent EphB4 signaling is anchoring signaling in glioma

Yosuke Kawahara¹; Takuya Furuta²; Hemragul Sabit¹; Yu Dong¹; Masahiro Oishi¹; Katsuyoshi Miyashita¹; Mitsutoshi Nakada¹

¹Department of Neurosurgery, Kanazawa University; ²Department of Pathology, Kurume University

Introduction: Despite the standard treatment of surgical resection of the glioblastoma followed by radiation and chemotherapy, patient survival remains a challenge. Extensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma malignancy. The role of Eph‐ephrin tyrosine kinase is gradually cleared. However, EphB4 of which ligand is ephrinB2 has not been investigated in glioma yet. We sought to reveal the role of EphB4 in glioma.

Materials & methods: The expression of EphB4 receptor was assessed in glioma cell lines by western blotting. The consequences of EphB4 activation by its ligand, ephrin‐B2 were determined by migration and invasion assay. The alteration of signaling pathways induced by EphB4 activation was investigated by western blotting. Immunofluorescence staining was performed to detect the localization of EphB4 and ephrin‐B2 expressing cells.

Results: EphB4 was highly expressed in U87 and SNB19 glioma cell lines and phosphorylated by ephrin‐B2. EphB4 phosphorylation by ephrin‐B2 suppressed migration and invasion in U87 and SNB19 and downregulation of EphB4 using small interfering RNA negated the suppression of migration and invasion induced by ephrin‐B2. Stimulation of glioma cells with ephrin‐B2 reduced the phosphorylated Akt levels dose dependently, which was abrogated by siRNA for EphB4. EphB4‐positive cells existed only at the tumor core, whereas Ephrin‐B2‐positive cells existed both at invasive area and the tumor core.

Conclusions: Ligand dependent EphB4 signaling plays a role as stay there signaling. Extinction of its signaling promotes the release of tumor cell on its location.

S18‐2

ICOSLG‐mediated IL‐10 producing regulatory T cell expansion promotes progression of glioblastoma multiforme

Ryoichi Iwata¹; Mikio Hayashi²; Masato Maruyama³; Souichi Oe⁴; Tomoki Ito⁵; Masahiro Nonaka¹; Hisao Yamada⁴; Dianzani Umberto⁶; Ichiro Nakano⁷; Akio Asai¹

¹Department of Neurosurgery, Kansai Medical University, Osaka, Japan; ²Department of Cell Physiology, Institute of Biomedical Science, Kansai Medical University; ³Department of Anatomy and Brain Science, Kansai Medical University, Hirakata, Japan; ⁴Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan; ⁵First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan; ⁶Interdisciplinary Research Center of Autoimmune Diseases, Department of Health Sciences, A. Avogadro University of Eastern Piedmont, 28100 Novara, Italy; ⁷Department of Neurosurgery, The University of Alabama at Birmingham, USA

Background: Inducible T‐cell co‐stimulator ligand (ICOSLG) is a member of B7 family immune‐regulatory ligands, expression of which in cancer is implicated in disease progression by regulating anti‐tumor adaptive immunity. Although aberrant ICOSLG expression has been reported in glioma cells, underlying mechanisms promoting glioblastoma (GBM) progression remains elusive.

Methods: In the present study, we investigated a causal role of ICOSLG in GBM progression by analyzing ICOSLG expression in both human glioma tissues and the patient‐derived GBM sphere cells (GSCs), and further dissecting its immune modulatory effects and the underlying molecular mechanisms.

Results: Bioinformatics analysis and GBM tissue microarray showed that upregulation of ICOSLG expression is associated with poor prognosis in patients with GBM. Results of our study further indicated that ICOSLG expression was upregulated preferentially in mesenchymal (MES) GSCs but not in proneural (PN) GSCs in a TNF‐ α /NF‐κB‐dependent manner. Furthermore, ICOSLG expression of MES GSCs promoted IL‐10 producing CD4+ Foxp3+ regulatory T cell expansion. Knockdown of ICOSLG gene markedly reduced GBM tumor growth in immune competent mice, with a concomitant downregulation of IL‐10 levels in tumor microenvironment. Moreover, knock down of ICOSLG and ICOS‐Fc treatment prolonged the survival of immunocompromised mice bearing GSC‐derived mesenchymal GBM‐like tumor. Knockdown of ICOSLG decreased CD44 and vimentin in tumor.

Conclusion: Collectively, our results indicated that inhibition of the ICOSLG‐ICOS axis in GBM may provide a promising immunotherapeutic approach.

S18‐3

Olig2 positive Oligodendrocytes lineage cells induce chemo‐radioresisitant characteristics at the tumor border in glioblastomas

Takuichiro Hide¹; Yoshihiro Komohara³; Yuko Miyasato³; Hideo Nakamura²; Keishi Makino²; Motohiro Takeya³; Jun‐ichi Kuratsu³; Mukasa Akitake²; Shigetoshi Yano²

¹Department of Neurosurgery, Kitasato University School of Medicine; ²Department of Neurosurgery, Kumamoto University School of Medicine; ³Department of Cell Pathology, Kumamoto University School of Medicine

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo‐radioresistance and survive. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass by miRNA microarray. The top three miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathological oligodendrocyte lineage cells increased in the border. In 19 consecutive GBM samples that contained border tissues, Olig2+ cells were characteristically observed in the border region in all GBMs, From the results of Olig2 staining, GBMs were classified into two groups (high and low) based on the rate of Olig2+ cells in the tumor. Olig2^high cases (n = 10) showed many positive cells in the tumor and border, whereas Olig2^low cases (n = 9) showed few positive cells in the tumor, but many cells in the border. Cells positive for other oligodendrocyte lineage markers, such as O4, NG2, MBP, were also consistently found in the border region of Olig2^high and Olig2^low samples. These data suggest that most Olig2+ cells in the border region were OLCs. Medium cultured with oligodendrocyte progenitor cells (OPCs) induced stemness and chemo‐radioresistance in GBM cells, similar to that produced by FGF1, EGF. Thus, OPCs may form a glioma stem cell niche at the tumor border.

S18‐4

Detailed analysis of mutation change after treatment in glioblastoma

Kuniaki Saito¹; Saki Shimizu¹; Eriko Nozaki²; Keiichi Kobayashi¹; Satoshi Kume¹; Tomohiro Chiba³; Junji Shibahara³; Yoshiaki Shiokawa¹; Motoo Nagane¹

¹Department of Neurosurgery, Kyorin University Faculty of Medicine; ²Core laboratory for proteomics and genomics, Kyorin University Faculty of Medicine; ³Department of Pathology, Kyorin University Faculty of Medicine

Introduction: Glioblastoma (GBM) is poor‐prognosis cancer and tumor recurrence is inevitable despite intensive chemoradiotherapy. Thus, insights into the mechanism of tumor recurrence are critical for improved patient treatment. Here, we describe our integrated genomic analyses using next‐generation sequencing of the paired samples from initial and recurrent tumors.

Methods: We collected paired GBM samples in patients who recurred after temozolomide (TMZ) treatment. Mutation analysis of the cancer‐related genes was performed using Ion Ampliseq Cancer Hotspot Panel v2. In addition, MGMT promoter methylation and expression of mismatch repair (MMR) protein such as MLH1, MSH2, MSH6, and PMS2 were analyzed by pyrosequencing and Western blotting, respectively.

Results: Sixty tumor samples from 29 patients were included in this study. Mutation acquisition of cancer‐related genes was observed only in 12 (41%) patients while remaining 17 (59%) patients were mutationally stable even after TMZ treatment. Mutations were gained in 5 MGMT methylated tumors and 7 unmethylated. Remarkably, 70% of acquired mutations in MGMT methylated tumor were G:C to A:T at non‐CpG sites whereas only 8% in MGMT unmethylated tumors. In mutation gain group, MMR expression decreased significantly after treatment (p=0.012‐0.048). Furthermore, in contrast to MGMT unmethylated tumors, MGMT methylated tumors showed marked MMR inactivation (40% vs. 7.5%, p=0.078).

Conclusion: We showed different types of the mutation acquisition after TMZ treatment according to MGMT status, providing further insights into the mechanism of TMZ resistance to improve treatment of the patients with GBM.

Symposium 19: S19‐1

Biological function and therapeutic potential of somatic mutations in meningiomas

Christian Mawrin

Department of Neuropathology, University Hospital Magdeburg, Germany

Meningiomas comprise the most frequent intracranial primary tumors, and with aging population the incidence of meningiomas is likely to increase. Meningioma therapy largely relies on surgical removal, while in some cases radiation therapy is encountered as primary or additional option. Recent genetic advances have identified somatic mutations in genes such as TRAF7/KLF4, AKT1, and SMO. Together with the well‐known fundamental role of NF2 in meningioma development, the molecular characteristics of meningiomas are now on a solid basis. However, the true biological role of these somatic mutations for meningioma development and growth are not fully understood. Additionally, this holds true for their role in non‐surgical therapies. The use of in vitro and especially in vivo mouse models to model meningioma biology is mandatory to explore the value of these mutations for the natural course, as well as potential treatment modalities. The current knowledge derived from model systems for AKT1, KLF4, SMO, and NF2 will be presented and discussed.

S19‐2

Role of CD163 in meningioma progression

Shinya Tanaka^1,2; Hiromi Okada³; Yoshitaka Oda¹; Lei Wang^1,2; Masumi Tsuda^1,2

¹Department of Cancer Pathology, Hokkaido University Faculty of Medicine; ²Global Station for Soft Matter, GI‐CoRE, Hokkaido University; ³Department of Surgical Pathology, Hokkaido University Hospital

Background: CD163 is a 130‐kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients’ poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression.

Methods: First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163‐overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo.

Results: Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163‐overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor‐derived granulocyte colony‐stimulating factor (G‐CSF) production, which was confirmed by reverse‐transcription polymerase chain reaction and enzyme‐linked immunosorbent assay.

Conclusions: To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse‐transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G‐CSF in meningioma.

S19‐3

Update of Meningioma Classification and Genetics

Arie Perry

Department of Pathology, Division of Neuropathology, University of California, San Francisco (UCSF)

Accounting for up to 37% of all primary CNS neoplasms, meningioma is one of the most common diagnoses encountered in neurosurgical practice. It has long been appreciated that the two most important prognostic variables for meningioma patients are extent of surgical resection and histopathologic grade. Grading criteria have varied greatly over time, although the current 2016 WHO scheme is largely derived from data reported in two large Mayo Clinic series published in the late 1990s. Since that time, the clinicopathologic associations have been independently validated, despite the concerns raised by some that the grade II category has become too commonplace. The derivation of this grading scheme and remaining controversies will be discussed, along with the identification of rare but biologically distinct variants, such as clear cell (including SMARCE1 alterations), chordoid, papillary, and rhabdoid (including BAP1 alterations) meningiomas. In contrast to diffuse gliomas and embryonal neoplasms, integrated diagnoses are not currently endorsed by the WHO 2016. Nevertheless, recent genetic advances beyond the long established role of NF2 will be discussed and now include driver mutations associated with skull base meningiomas utilizing TRAF7/KLF4 (including secretory meningioma), AKT, and SMO genes. The expanding list of biomarkers for tumor progression and aggressive biology now also includes Ki‐67 LI, progesterone receptor expression, homozygous CDKN2A gene deletion, other copy number alterations, pTERT mutations, and epigenetic patterns, such as H3K27me3 loss and methylation profiling signatures.

S19‐4

Radiation‐induced meningiomas: experience at the Hiroshima University Hospital and review of the literature

Fumiyuki Yamasaki¹; Takeshi Takayasu¹; Motoki Takano¹; Ushio Yonezawa¹; Kazuhiko Sugiyama²; Kaoru Kurisu¹

¹Department of Neurosurgery, Hiroshima University Hospital, Hiroshima, Japan; ²Clinical Oncology & Neuro‐oncology Program, Hiroshima University Hospital, Hiroshima, Japan

Secondary meningioma after cranial irradiation (i.e. radiation‐induced meningioma) is considered as an uncommon late risk of cranial irradiation. We previously reported that the incidence of meningioma for atomic bomb radiation doses >0.1 sievert, or the exposed patients at distance of <2.0 km from epicenters was statistically higher than non‐exposed group (P<0.005). The risk of secondary meningioma development was shown to increase with closer proximity to the atomic bombs’ epicenters and in those exposed during childhood. It is now well‐known that the increase incidence of meningioma is the delayed side effects of not only atomic bomb radiation exposure but also cranial/craniofacial irradiation for malignancy.

In this report, we present our experience of secondary meningioma after cranial irradiation. Between 2000 to 2018, we radiologically diagnosed 8 patients with meningioma after cranial irradiation at the dose of 15 to 60Gy. Seven of 8 patients were surgically confirmed for the development of meningioma. Three patients had multiple meningiomas, and 4 patients had complicated cavernous angiomas. The mean age of the patients was 35 years (median 32) and the mean tumor latency was 18.4 years (median 18.3). Histopathology revealed the higher incidence of grade II & III meningiomas (3 atypical, 1 papillary subtype). We review the typical presentation of patients with secondary meningioma after cranial irradiation and discuss unique aspects of the clinical management of these tumors compared with sporadic meningioma, based on our clinical experience and literature review in treating these lesions.

Symposium 20: S20‐1

Irradiated brain parenchyma provides favorable microenvironments for glioma stem cells to maintain their tumor‐propagating ability

Naosuke Nonoguchi¹; Masashi Yoshikawa¹; Yuichiro Tsuji¹; Nobuhiko Yoshikawa²; Taichiro Touho³; Oltea Sampetrean⁴; Ryohei Yamamoto⁵; Motomasa Furuse¹; Hideyuki Saya⁴; Toshihiko Kuroiwa¹

¹Department of Neurosurgery, School of Medicine, Osaka Medical College, Takatsuki, Japan; ²Department of Radiology, School of Medicine, Osaka Medical College, Takatsuki, Japan; ³Tohou Neurosurgical Clinic, Osaka, Japan; ⁴Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan; ⁵Department of Advanced Pathobiology, Graduate School of Life & Environmental Sciences, Osaka Prefecture University, Sakai, Japan

Despite of aggressive multimodal treatment for patients with glioblastoma (GBM), the tumor recurrence is still a leading cause of mortality. In our previous studies using a rodent model of chronic cerebral radiation injury, whole transcriptome analysis revealed that, 3‐6 month after X‐ray irradiation, various gene pathways were significantly affected and became altered in the irradiated brains. Clinically, this would occur also in a patient's brain where surviving tumor cells are lurking. In the present study, therefore, we hypothesized that the pathophysiological changes raised in brain parenchyma by radiotherapy may involve in the tumor recurrence of GBM. We implanted TS cells, a B6 mouse glioma stem cell (GSC) line, into B6 mice brains which were locally irradiated by 60 Gy of X‐ray, 3 months prior to the tumor implantation. Gliomas formed in the pre‐irradiated and naive brains (control) were removed and minced for single cell isolation to recover alive tumor cells. In FACS analyses, the mean percentages of cells expressing CD133 and Nestin were significantly higher in the tumors from the pre‐irradiated brains than those from naive brains; CD133: 78.6% vs 12.6% and Nestin: 25.8% vs. 8.7%, respectively (p<0.01). Next, we transplanted these isolated tumor cells into naive mice brains. The animals implanted with the tumor cells from pre‐irradiated brain showed significantly shorter survival than the animals with the control cells (Median survival: 15 vs. 20 days, p<0.0001). Collectively, our data suggest that irradiated brain parenchyma might afford a favorable microenvironment to maintain the stemness in surviving GSCs after radiotherapy.

S20‐2

Mining‐guided future prediction‐The 20 hottest neuro‐oncological fields in 2019

Taijun Hana^1,2; Shota Tanaka¹; Satoshi Takahashi¹; Tsukasa Koike¹; Yosuke Kitagawa¹; Takahide Nejo¹; Masashi Nomura¹; Shunsaku Takayanagi¹; Nobuhito Saito¹

¹Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ²Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Background: Grasping objective trends in today's rapidly changing academic fields is important. We analyzed the trends of brain tumor articles with our novel algorithm and predicted the 20 hottest neuro‐oncological fields in 2019.

Method: Text‐mining analyses were performed to whole MeSH data of all brain tumor articles published in 2017, and to particularly chosen text data of international conferences held in 2017. Sixty‐nine frequently used keywords and 10 important brain tumor diagnoses comprised the subject fields of our survey. We chose the 15 highest impact factor (IF) journals among 8014 journals that have published neuro‐oncological articles in 2017. In addition, we found 15 journals that had the largest number of published articles in 2017. These 30 journals were the subject journals of our survey. The annual impact (AI) of each year was calculated for each journal and each field (number of articles published in the journal × IF of the journal). A field's AI index (AII) for the year was the sum total of AIs of each of the 30 journals. The AII trends of the 79 subject fields during 2008‐2017 were analyzed with linear approximations. With the above algorithm, the 20 hottest neuro‐oncological fields in 2019 were predicted.

Results: The 20 predicted fields comprise not only widely recognized fields such as immuno‐oncology and epigenetics, but also emerging fields such as microenvironment.

Conclusion: This algorithm can be an effective tool for future prediction of medical field.

S20‐3

Tpr is an autophagy induced cell death suppressor in ependymoma

Sabit Hemragul¹; Jiapaer Shabierjiang¹; Tamai Sho¹; Devi Firli Rahmah Primula²; Hazawa Masaharu²; Kobayashi Akiko²; Wong Richard²; Nakada Mitsutoshi¹

¹Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan; ²Laboratory of Molecular and Cellular Biology, Department of Biology Faculty of Natural Systems, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

Background: The nuclear pore complex (NPC) is composed of around 30 proteins and resides in the nuclear envelope. NPC regulates gene‐expression, chromosomal division, and autophagy beyond nucleocytoplasmic transport, sustaining a life of the cell. Recent genomic analysis identified Tpr (translocated promoter region), one of NPC components, as an amplified gene in ependymoma. However, the significant role of Tpr in ependymoma is poorly understood. Previously, we reported that Tpr is highly expressed in ependymoma patients. Further, we verified that Tpr is required for malignant behavior by xenograft assay. We will present molecular mechanism regulated by Tpr in ependymoma.

Method: Samples from ependymoma patients and ependymoma cell line Vn19 were used. To measure autophagy activity, we employed qRT‐PCR and Western Blot analysis. Further, immune‐fluorescent imaging was performed to analyze autophagosome formation processes.

Results: Ependymoma patients showed lower mRNA levels of autophagy molecules (BECN1, ATG3, ATG5, ATG7, ATG12). Further, protein levels of LC3B were reduced in ependymoma patients. The siRNA‐mediated Tpr depletion resulted in the increase of autophagy molecules in Vn19. Finally, confocal‐microscopy analysis using Vn19 silenced Tpr or expressing LC3‐GFP determined autophagosomes were formed inside nuclear.

Conclusion: Tpr suppresses nucleophagy activation and mediates ependymoma malignancy.

S20‐4

The correlation between 1p19q and TERT promoter mutation status in IDH‐mutant gliomas

Nobuhiro Hata¹; Masahiro MIizoguchi¹; Yojiro Akagi¹; Satoshi O Suzuki²; Daisuke Kuga¹; Takeo Amemiya¹; Ryusuke Hatae¹; Koji Yoshimoto³; Toru Iwaki²; Koji Iihara¹

¹Department of Neurosurgery, Kyushu University; ²Department of Neuropathology, Kyushu University; ³Department of Neurosurgery, Kagoshima Univeristy

Background: The revised WHO 2016 classification established the consensus that the diagnosis of oligodendrogliomas should be confirmed by IDH mutation and 1p19q codeletion. As these tumors are known to harbor TERT promoter mutation also, TERT status seems to be useful as a surrogate marker for 1p19q. Herein, we aim to verify this theory by analyzing the correlation between 1p19q and TERT status.

Methods: IDH and TERT status were determined by Sanger sequencing. 1p19q codeletion was confirmed by LOH on total arms using multiple microsatellite markers. We reviewed our case series of 65 gliomas with IDH mutation whose 1p19q and TERT status were examined.

Results: Whereas 60 out of 65 showed the consistency of 1p19q and TERT status, the remaining 5 were 1p19q non‐codel/TERT mutant. In these 5 cases, 3 showed consistent clinical, radiographic and pathological features of oligodendroglioma. In contrast, the pathological diagnoses of the remaining 2 were anaplastic astrocytoma and glioblastoma, both of which also showed astrocytic molecular findings.

Conclusion: This study seems to support the theory that, in general, TERT mutation can be used as an effective surrogate marker of 1p19q for IDH mutant gliomas. Although, there were a few exceptional cases, thereby, we need further efforts to elucidate the correlation between 1p19q and TERT status.

S20‐5

Clinico‐pathological findings of 1p19q LOH by using FISH method in high grade glioma : With findings of MLPA

Kenichiro Asano¹; Akihisa Kamataki²; Kaoru Ogawa²; Toshio Fumoto¹; Kosuke Katayama¹; Kiyohide Kakuta¹; Hiroki Ohkuma¹; Akira Kurose²

¹Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan; ²Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Aomori, Japan

Introduction: Integrated diagnosis for G2 or G3 oligodendroglial tumor is needed to proof both IDH mutation and 1p/19q‐codeletion. However, we sometimes experienced 1p/19q‐codeletion, 1p or 19q LOH in high grade glioma by using FISH. We have some questions why high grade gliomas sometimes have 1p or 19q LOH. Then, we compared in clionico‐pathological findings.

Material and method: We pick up consecutive operation cases in 2016˜2018. Median age was 55yo, 18 cases of GBM IDH‐wildtype, 1case of GBM IDH‐mutant, 9 cases of AA IDH‐mutant, and 6 cases of AO IDH‐mutant and 1p/19q‐codeleted were eliminated. After ordinal pathological findings, we examined sequences, FISH, and MLPA. Probe of FISH was LSI1p36/LSI1q25,LSI19q13/19p13, and one of MLPA was SALSA MLPA P088‐C2 Oligodendroglioma 1p‐19q probemix.

Result: We defined the cutoff point 20% of 1p19qLOH, 13 cases of high grade gliomas without AO IDH‐mutant and 1p/19q‐codeleted. In these cases, 5 cases were codeleted 8 cases were 1p or 19q LOH. There was no close relations between these cases and GBM IDH‐wildtype in pathological findings of calcification, peri‐nuclar halo, chicken‐wire like vessels, microvascular proliferation, pseudoparisading, MGMT methylation status, and MIB‐1. We tested MLPA method for these high grade glioma, and 1p or 19q point or hole deletion were seen acutually. Prognosis depended on integrated diagnosis.

Conclusion: Even though 1p/19q‐codeleted was proofed by FISH, MLPA would showed a point or hole deletion, and biological behavior depended on the integrated diagnosis clinic‐pathologically.

S20‐6

Detection of 1p19q codeletion by targeted sequencing for glioma genotyping

Yasutaka Kato^1,3; Emmy Yanagita¹; Lei Wang²; Eriko Aimono¹; Shinya Tanaka²; Hiroshi Nishihara^1,3

¹Genomics Unit, Keio Cancer Center, Keio University School of Medicine; ²Department of Cancer Pathology, Hokkaido University Faculty of Medicine; ³Cancer Research Institute, Hokuto Hospital

Detailed genotyping for glioma detecting the mutation in IDH1/2, ATRX, p53, TERT promoter region in addition to 1p19q codeletion is mandatory for final diagnosis especially for selecting the treatment after surgery. Here we established rapid and valuable targeted sequence pipeline for glioma genotyping for not only SNV detection but also 1p19q codeletion. Capture sequencing panel targeted 16 genes including ATRX, IDH1, IDH2, TP53, TERT were designed by SeqCap EZ target enrichment system (Roche). Genomic DNA was extracted from surgically resected glioma tissue (FFPE; formalin fixed paraffin embedded, or PFPE; PAXgene fixed paraffin embedded) and the libraries were sequenced by the MiSeq (Illumina). The raw read data obtained from amplicon sequencing were processed by originally designed, dedicated analysis pipeline by Genome Jack (Mitsubishi Space Software Inc.) We detected IDH1 R132H mutation in 3 out of 9 grade II‐IV gliomas by our sequence pipeline, while IHC for IDH1 R132H was positive in 5 cases including these 3 cases. Our sequence pipeline and also FISH identified 1p19q codeletion only in these 3 cases with IDH1 R132H mutation positive, thus we concluded that the other two IHC‐positive cases were false positive. Moreover, we successfully detected LOH of PTEN and amplification of EGFR and MET. Our workflow can be finished within 7 working days with reasonable cost, offering a practical laboratory developed test for glioma genotyping.

Symposium 21: S21‐1

Intracranial remote recurrence in IDH mutant gliomas is associated with TP53 mutations and 8q gain

Shunsuke Nakae¹; Takema Kato²; Kazuhiro Murayama³; Hikaru Sasaki⁴; Masanobu Kumon¹; Shigeo Ohba¹; Mitsuhiro Hasegawa¹; Hiroki Kurahashi²; Yuichi Hirose¹

¹Department of Neurosurgery, Fujita Health University; ²Fujita Health University Institute for Comprehensive Medical Science, Division of Molecular Genetics; ³Fujita Health University, Department of Radiology; ⁴Keio University, Department of Neurosurgery; ⁵Fujita Health University, Department of Pathology

Most IDH mutant gliomas harbor either 1p/19q co‐deletions or TP53 mutation, and 1p/19q co‐deleted tumors (oligodendrogliomas) demonstrate significantly better prognoses than tumors harboring TP53 mutations (astrocytomas). To investigate clinical factors which contribute to the difference in tumor progression of the IDH mutant groups, we classified the tumor recurrent patterns based on MRI, and correlated this with genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), almost all 1p/19 co‐deleted gliomas showed local recurrence, whereas TP53 mutant gliomas showed intracranial remote recurrence, as well as local recurrence. In addition, diffuse tensor imaging suggested that intracranial remote recurrence in the astrocytomas, IDH‐mutant with TP53 mutations may occur along major fiber bundles. The remotely recurrent tumors showed a higher mortality and significantly harbored an 8q gain; astrocytomas with the 8q gain revealed a significantly shorter overall survival than those without the 8q gain. Next‐generation sequencing indicated that the specific regions of 8q (i.e., between 8q22 and 8q24) show a high copy number. In conclusion, only tumors with TP53 mutations showed a distant recurrent pattern in IDH mutant gliomas. Furthermore, 8q gain was significantly associated with intracranial remote recurrence and can be considered as a poor prognostic factor in astrocytomas, IDH‐mutant.

S21‐2

A phase I/IIa clinical trial of Ad‐SGE‐REIC for malignant glioma

Kazuhiko Kurozumi¹; Kentarou Fujii¹; Tetsuo Oka¹; Toshihiko Shimizu¹; Yusuke Tomita¹; Yasuhiko Hattori¹; Kumon Hiromi²; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ²Innovation Center Okayama for Nanobio‐targeted Therapy, Okayama University, Okayama, Japan

Expression of the gene encoding reduced expression in immortalized cells/Dickkopf‐3 (REIC/Dkk‐3) was shown to be reduced in a variety of human cancer cells. We investigated the anti‐glioma effect of an adenoviral vector carrying REIC/Dkk‐3 gene (Ad‐CAG‐REIC). We also recently developed a novel adenoviral vector (Ad‐SGE‐REIC), which could express more REIC/Dkk‐3 protein than Ad‐CAG‐REIC. We evaluated the anti‐glioma effect of Ad‐SGE‐REIC against malignant glioma in vitro and in vivo. In the cytotoxicity assay of malignant glioma cell lines (U87dEGFR and GL261), after treatment with Ad‐SGE‐REIC, the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time‐dependent manner. Mice treated with Ad‐SGE‐REIC survived significantly longer than mice treated with Ad‐LacZ or Ad‐CAG‐REIC, demonstrating promising anti‐glioma activity for Ad‐SGE‐REIC. We conducted toxicology tests using intracranial injection of higher doses of Ad‐SGE‐REIC for Shinnihon Kagaku Mfg., Ltd. We aim to submit notification of a plan for a phase I/II clinical trial of Ad‐SGE‐REIC for the treatment of malignant brain tumor this year. This will be an open‐label, single‐armed, phase I/II study involving three cohorts of three or six subjects each in the dose‐escalation phase. This Ad‐SGE‐REIC may help to improve the prognosis for patients with malignant gliomas.

S21‐3

IDH gene status is associated with pattern of relapse in malignant gliomas

Yukihiko Sonoda¹; Ichiyo Shibahara^2,3; Tetsu Yamaki¹; Ryuta Saito²; Ken‐Ichiro Matsuda¹; Masayuki Kanamori²; Toshihiro Kumabe^2,3; Teiji Tominaga²

¹Department of neurosurgery, Faculty of Medicine, Yamagata University, Yamagata, Japan; ²Department of Neurosurgery, Tohoku University Graduate School of Medicine; ³Department of Neurosurgery, Kitasato University School of Medicine

Introduction: Since the local recurrence was found in majority of malignant glioma, the patients received local irradiation around resection cavity. However, the distant recurrence sometimes occurred without local recurrence. In this study, we analyzed the association of the pattern of recurrence and molecular alterations.

Methods: We retrospectively analyzed 245 cases of malignant gliomas (WHO grade III: 86 cases, Grade IV: 159 cases). Data regarding patient characteristics, recurrence pattern, and prognosis were obtained from medical records. We examined molecular alterations such as IDH mutation, 1p19q loss, TP53 gene mutation.

Results: Of the 86 patients with anaplastic gliomas, 58 carried IDH mutation, and 40 experienced recurrence. The first recurrence was local in 25 patients and distant in 15. Patients without IDH mutation showed more frequent distant recurrence than those with IDH mutation. P=0.022). No distant recurrence was found in the tumor with IDH1 mutation and 1p/19q co‐deletion. On the other hand, of the 159 patients with glioblastomas, 4 carried IDH mutation, and 127 experienced recurrence. The first recurrence was local in 99 patients and distant in 28. No Patients with IDH mutation showed distant recurrence.

Conclusion: IDH gene status is the strong predictor for recurrence pattern in malignant gliomas.

S21‐4

An important role of histopathology and immunohistochemistry in immunotherapy against high grade gliomas

Naoya Hashimoto¹; Yoshinobu Takahashi¹; Kazunori Tatsuzawa¹; Chisato Yokota²; Yasuyoshi Chiba²; Naoki Kagawa²; Yasunori Fujimoto²

¹Department of Neurosurgery, Kyoto Prefectural University of Medicine Graduate School of Medical Science; ²Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

We have conducted WT1 peptide immunotherapy against high grade gliomas in some investigator‐initiated clinical trials. Safety and efficacy of the therapy were reported and nowadays sponsor‐initiated trials are on‐going. In this paper, a role of histopathology and immunohistochemistry was focused and reviewed.To enroll the clinical trials, the patient must have matched HLA type and tumor cells must have positive WT1 expression. After the basic research revealed the correlation between mRNA level and WT1 expression in immunohistochemistry, we have used the WT1 immunohistochemistry with WT1 6F‐H2 antibody to judge the enrollment of each patient to the clinical trials. Accordingly, we created WT1 score for positivity evaluation and revealed that the patients with WT1 score 3, 4 (strong expression) survive longer than those with WT1 score 1, 2 (weak), concluding that WT1 score by immunohistochemistry can be a predictive factor. Gathering the data on the WT1 immunohistochemistry, a working group in the international conference on WT1 in human neoplasia advocated an international harmonization on immunohistochemical evaluation of WT1 positivity in solid cancers in 2012. Further, we have conducted immunohistochemistry using antibody of WT1 / HLA / various cytokines, and subset markers of tumor infiltrating lymphocytes (TIL). By comparing those expressions on pre‐ and post‐ immunotherapy surgical samples, we found some mechanisms of escape phenomenon of tumor cells from immunotherapy.An important role of histopathology and immunohistochemistry will be summarized in the presentation.

S21‐5

MGMT promoter methylation in patients with glioblastoma multiforme: Is methylation‐sensitive high‐resolution melting superior to methylation‐sensitive polymerase chain reaction assay?

Shinji Yamashita; Kiyotaka Yokogami; Kiyotaka Saito; Fumitaka Matsumoto; Asako Mizuguchi; Takashi Watanabe; Hajime Ohta; Hideo Takeshima

Division of Neurosurgery, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki

The methylation status of O6‐methylguanine‐DNA methyltransferase (MGMT) gene promoter is not only the predictive marker in adult glioblastoma (GBM) but also acts as an information useful for clinical decision‐making in elderly patients with GBM. Although pyrosequencing analysis has been introduced as the gold standard for evaluating the methylation status of MGMT, many institutions and studies still employ methylation‐specific polymerase chain reaction (MSP) since this method is cost‐effective and does not require special analyzers. Although MSP shows good correlation with the prognosis of GBM patients treated with Stupp protocol, it has some limitations, such as ambiguity in judgment and non‐applicability for evaluating heterogeneously methylated samples. In this study, we focused on the methylation‐sensitive high‐resolution melting (MS‐HRM) for an alternative to MSP. The methylation levels of 6 glioma cell lines were estimated by MS‐HRM, and the data was validated by the bisulfite sequencing of cloned alleles. Strong correlation was observed between MS‐HRM and bisulfite sequencing, indicating that MS‐HRM could be a reliable method for estimating methylation levels (Correlation coefficient for #1 primer: 0.959 and #2 primer: 0.960). Methylation levels of 75 samples from patients with GBM were estimated using MS‐HRM and compared to that of the MSP data. MS‐HRM is superior to MSP in discriminating between responders and non‐responders to temozolomide (TMZ) (p value of log‐rank test, PFS; MS‐HRM: 0.00023, MSP: 0.0035, OS; MS‐HRM: 0.00019, MSP: 0.00028). Taken together, our study suggests that MS‐HRM is a superior method for detecting MGMT promoter methylation status as compared to MSP.

S21‐6

A subgroup of IDH‐mutated astrocytomas with 19q‐loss presents oligodendroglioma‐like morphology and better prognosis

Ryohei Otani^1,2; Takeo Uzuka²; Fumi Higuchi²; Hadzki Matsuda^2,6; Masashi Nomura³; Shota Tanaka³; Akitake Mukasa⁴; Koichi Ichimura⁵; Phyo Kim²; Keisuke Ueki²

¹Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ²Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan; ³Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ⁴Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ⁵National Cancer Center Japan, Tokyo, Japan; ⁶Department of Pathology, Dokkyo Medical University, Tochigi, Japan

IDH‐mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in WHO 2016 classification, with the latter presenting with characteristic morphology and show better prognosis in general. However, the morphological and genetic features within 1p/19q intact astrocytomas are varied, and there may be distinguishable subtype. We analyzed gliomas with only 19q‐loss in 170 WHO grade II to IV gliomas. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next‐generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of the TCGA was analyzed. Of the 42 grade III IDH‐mutated gliomas, 12 were 1p‐intact/19q‐intact (anaplastic astrocytomas: AA), 7 were 1p‐intact/19q‐loss (AA), and 23 showed 1p/19q‐codeletion (anaplastic oligodendrogliomas: AO). All of the seven 1p‐intact/19q‐loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q‐loss AAs had regions presenting oligodendroglioma‐like morphology, and were associated with significantly longer overall survival (OS) compared to 19q‐intact AAs (p=0.001). This tendency was observed in the TCGA Lower Grade Glioma dataset. In contrast, there was no difference in OS between the 19q‐loss GBM (n=14) and 19q‐intact GBM (n=74) (p=0.4). In a case of 19q‐loss AA, both oligodendroglial morphology and 19q‐loss disappeared after recurrence, possibly indicating correlation between 19q‐loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH‐mutated astrocytomas harboring 19q‐loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q‐intact astrocytomas.

S21‐7

Usefulness and pitfalls of 1p/ 19q‐codeletion analysis by FISH method in glioblastoma

Hiroyuki Uchida; Hajime Yonezawa; Hirofumi Hirano; Koji Yoshimoto

The Department of Neurosurgery, University of Kagoshima, Kagoshima, Japan

Objective: According to the revision of WHO classification, diagnosis of glioblastoma is accompanied by the status of IDH‐mutation. However, when it is necessary to differentiate from anaplastic oligodendroglioma, information of 1p/ 19q‐codeletion is also required. We examined the usefulness and problems of fluorescence in situ hybridization (FISH).

Methods: Of the 242 diffuse glioma cases in which 1p/ 19q‐codeletion was searched by FISH since 2009 to 2016, 141 cases of primary glioblastoma were analyzed. Vysis LSI DNA probe 1p36/ 1q25 and 19p13/ 19q13 were used as probes, and the cutoff value was set at 20%.

Results: When judging that there was deletion when the signals of 1p or 19q were less than the signals of 1q or 19p respectively, 33 cases in 1p‐deletion and 18 cases in 19q‐, codeletion was 6 cases . On the other hand, when judging that deletion was present only when single signal of 1p or 19q and two signals of 1q or 19p were detected, 12 cases in 1p‐deletion and 6 cases in 19q‐, codeletion was one case.

Discussion: Although in glioblastoma there are many atypical deletion patterns compared to oligodendroglial tumor, they should not be judged as deletion. Since the case with codeletion had a histological feature of glioblastoma, FISH might detect partial deletion of 1p36, then it is necessary to interpret combined with the status of IDH‐mutation. Conclusion: In differentiating between glioblastoma and anaplastic oligodendroglioma, 1p/ 19q‐codeletion analysis by FISH can be useful with consideration of its pitfalls.

S22‐1

Insights from Studies of The Acquired Tauopathies

Daniel P Perl

The Center for Neuroscience and Regenerative Medicine’s Brain Tissue Repository, Uniformed Services University of the Health Sciences

Virtually all of the major disorders seen in adults, such as cancer and atherosclerosis leading to myocardial infarction, represent complex interactions between genetic and environmental factors. I will discuss insights gained from studying three examples of acquired (environmental) tauopathies, namely post‐encephalitic parkinsonism (PeP), ALS/parkinsonism‐dementia complex of Guam (ALS/PDC) and chronic traumatic encephalopathy (CTE). PeP followed a pandemic of encephalitis early in the 20th century, where 50% of affected patients died from the acute illness. A very high percentage of the survivors developed progressive parkinsonism (PeP), characterized by numerous neurofibrillary tangles (NFTs). ALS/PDC occcurs among the Chamorro natives of Guam and involves ALS as well as a form of parkinsonism accompanied by progressive dementia (PDC). Affected patients show motor and SNc neuron neurodegeneration with widespread NFT involvement. Recently ALS/PDC has dramatically decreased in prevalence, confirming its environmental etiology. CTE is a disorder seen following repeated inpact traumatic brain injuries, especially among contact sport participants. It is characterized by widespread tau pathology in the form of NFTs, astrocytic tangles and tau threads in a characteristic pattern not shared by other forms of tauopathy. These three disorders provide insights into the environmental side of nature/nurture interactions leading to neurodegeneration although the mechanism/s underlying this phenomenon remains unclear. For non‐neurologic diseases, avoiding relevant environmental factors represents an effective means to reduce prevalence. Robust inquiries into environmental factors in neurodegenerative disease could represent an effective means by which the impact of these conditons could also be reduced.

S22‐2

Consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

Nigel J. Cairns¹; Ann C. McKee^2,3,4,5,6; Dennis W. Dickson⁷; Rebecca D. Folkerth⁸; C. Dirk Keene⁹; Irene Litvan¹⁰; Daniel P. Perl¹¹; Thor D. Stein^3,4,5,6; Jean‐Paul Vonsattel¹²; William Stewart¹³; Yorghos Tripodis^4,14; John F. Crary¹⁵; Kevin F. Bieniek⁷; Kristen Dams‐O'Connor¹⁶; Victor E. Alvarez^2,3,4,5; Wayne A. Gordon¹⁶; the TBI/CTE group

¹Department of Neurology, Washington University, Saint Louis, Missouri, USA; ²Department of Neurology, Boston University School of Medicine, Boston, USA; ³Department of Pathology, Boston University School of Medicine, Boston, USA; ⁴Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, USA; ⁵VA Boston Healthcare System, Boston, USA; ⁶Department of Veteran Affairs Medical Center, Bedford, USA; ⁷Department of Neuroscience, Mayo Clinic, Jacksonville, USA; ⁸Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA; ⁹Department of Pathology, University of Washington School of Medicine, Seattle, USA; ¹⁰Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, USA; ¹¹Department of Pathology, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, USA; ¹²Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University Medical Center, New York, USA; ¹³Department of Neuropathology, University of Glasgow Institute of Neuroscience and Psychology and Queen Elizabeth University Hospital, Glasgow, UK; ¹⁴Department of Biostatistics, Boston University School of Public Health, Boston, USA; ¹⁵Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai School, New York, USA; ¹⁶Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, USA

Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, CTE can only be definitively diagnosed by post‐mortem examination of brain tissue. A consensus panel funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS/NIBIB) was convened to define the neuropathological criteria for CTE.

Methods: Twenty‐five cases of various tauopathies were selected. The cases included 10 cases of suspected CTE and other cases that may have overlapped or be confused with CTE included Alzheimer disease (n=5), progressive supranuclear palsy (n=2), corticobasal degeneration (n=2), parkinsonism/dementia complex of Guam (n=2), argyrophilic grain disease (n=2), and primary age‐related tauopathy (n=2). From 27 representative areas, sections were stained with Luxol fast blue counterstained with hematoxylin and eosin and a Bielschowsky silver impregnation; immunohistochemistry was performed using anti‐Aβ42, anti‐phosho‐tau and anti‐phospho‐TDP‐43. The 671 glass slides were scanned into digital images using an Aperio scanner (Leica Biosystems, Buffalo Grove, IL. No clinical or demographic information was provided to the evaluating neuropathologists.

Results: There was good agreement regarding the overall neuropathological diagnosis of all 25 cases (Cohen's kappa, 0.67), and even better agreement regarding the specific diagnosis of CTE (Cohen's kappa, 0.78), using the proposed criteria. Three initial diagnoses of non‐CTE were changed to CTE and nine diagnoses of co‐morbid CTE in non‐CTE cases were changed to no CTE after revealing the clinical and gross neuropathological features.

Conclusion: A consensus panel of seven neuropathologists concluded that the pathology of CTE is distinct from other tauopathies. The panel described the pathognomonic lesion of CTE as an accumulation of abnormal tau in neurons and astroglia distributed perivascularly at the depths of sulci in the isocortex in an irregular pattern.

S22‐3

Chronic Traumatic Encephalopathy in Athletes: The Aftermath of Repetitive Head Injuries

Kathy L Newell

Department of Pathology & Laboratory Medicine, University of Kansas Medical Center

Chronic traumatic encephalopathy (CTE), a brain disorder characterized by the intracytoplasmic accumulation of misfolded tau in neurons and glia, has been recognized to be caused by the repetitive head traumas associated with the practice of several types of contact sports. In the 1920‐30's, descriptions of the “punch drunk“ neurological syndrome of professional pugilists were reported, and the first neuropathologic descriptions of boxers’ brains were published 30‐40 years later. The macroscopic and microscopic findings consisted of abnormalities of the septum pellucidum, cerebellar scarring, neurofibrillary degeneration, particularly severe in the temporal lobes, and degeneration of neurons of the substantia nigra and locus coeruleus. As early as the 1880's, concussions among college football players were already of concern; however, it was not until the mid 2000's that autopsies of former professional football players revealed the neuropathologic features of CTE, linking tau pathology to repetitive head injuries in footballers. CTE has recently been described in association with other sports, including soccer, rugby, mixed martial arts, and hockey. In 2016, neuropathologic criteria for CTE were established. In contrast to other tau pathologies, the spatial distribution of perivascular tau aggregates in neurons and glia, notably at the depth of sulci, is considered pathognomonic. Impact‐injuries and distribution of brain changes may differ among athletes due to differences in the mechanisms of and/or risks for head injuries relevant to each sport. Individual genetic risks for the development of CTE may also contribute. At present, a definitive diagnosis of CTE is made only through postmortem neuropathology. However, Tau‐PET neuroimaging and other biomarkers may lead to CTE diagnosis during life, possibly during early, even clinically silent, stages of disease. Biomarkers of early stages of neurodegeneration may be useful to recognize clinical stages of CTE and help identify individuals at risk for CTE for early treatment when novel therapies become available.

S22‐4

Neuropathology of Familial Amyotrophic Lateral Sclerosis and Parkinsonism dementia Complex from the Hohara focus of the Kii Peninsula: a tau‐dominant multiple proteinopathy

Maya Mimuro¹; Mari Yoshida¹; Shigeki Kuzuhara²; Yasumasa Kokubo³

¹Institute for Medical Science of Aging, Aichi Medical University; ²Faculty of Nursing, Suzuka University of Medical Science; ³Kii ALS/PDC Research Center, Mie University Graduate School of Regional Innovation Studies

The Kii peninsula of Japan is one of the high incidence foci of amyotrophic lateral sclerosis (ALS) and parkinsonism‐dementia complex (PDC) in the Western Pacific. Recently, Kii ALS/PDC is considered as a heterogeneous syndrome of several different causes including both genetic and environmental factors. In this symposium, we present the neuropathology of familial cases of ALS/PDC from Hohara, the eastern focus of Kii ALS/PDC, which is characterized tau‐dominant multiple proteinopathy. Eighteen cases were submitted for this study. Clinically, they showed motor neuron signs and/or parkinsonism with dementia. Pathologically, their brains showed accumulation of various proteins, including tau, TDP‐43, and alfa‐synuclein (α Syn).NFTs were predominantly found in the superficial layers of the cerebral cortex and ghost tangles were abundant. Neuropil threads were scarce compared with Alzheimer's brains.Tau‐positive astrocytes were observed mainly at subpial and perivascular regions. Tau deposition in both neurons and astrocytes were the common neuropathological features of all cases. pTDP‐43‐positive neuronal cytoplasmic inclusions were observed in all brains, mainly in the limbic system. Bunina bodies and skein‐like inclusions were observed in 65%, and Lewy body pathology, in 77% of them. Among them, cases with pTDP‐43‐predominant deposition clinically showed signs of ALS, while cases with α Syn‐predominant deposition showed signs of PDC. From the above findings, we have concluded that ALS/PDC from Hohara is a single familial disease characterized by tau‐dominant multiple proteinopathy though clinical manifestations differed among the cases.

Symposium 23: S23‐1

Axonal Pathology in Multiple Sclerosis

Hans Lassmann

Center for Brain Research, Medical University of Vienna

Multiple sclerosis is a chronic inflammatory disease of the central nervous system leading to focal plaques of demyelination and diffuse neurodegeneration in the brain and spinal cord. Although demyelination is the hallmark of MS pathology, axons degenerate within the lesions and diffusely in the normal appearing white and grey matter. Axonal loss is a major structural correlate of permanent functional deficit in the patients. In focal white matter lesion the bulk of axonal injury occurs during the stage of active demyelination. In addition, however, there is a slowly progressive axonal injury in chronic demyelinated plaques, which is massively reduced or even absent, when the lesions are remyelinated. Axonal and neuronal degeneration in the lesions of the white and grey matter results in secondary Wallerian degeneration in the normal appearing white and grey matter, thus providing a major contribution to global axonal loss and atrophy in the brain and spinal cord. In addition, acute axonal injury and neuronal degeneration also takes place independent of focal demyelinated lesions, being associated with inflammation in the meninges, in the large perivascular spaces and in the central nervous system parenchyma. A variety of different mechanisms have been suggested to drive axonal and neuronal degeneration in MS, including T‐cell mediated cytotoxicity, autoantibodies and activation of innate immune mechanisms. A prominent pathogenic cascade of neurodegeneration in MS involves oxidative stress, resulting in mitochondrial damage and subsequent energy failure. Neurodegeneration through this mechanism is amplified by the increased energy demand of demyelinated axons.

S23‐2

Oligodendrocyte pathology in MS

Wolfgang Brück

Institute of Neuropathology, University Medical Center Goettingen, Germany

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to focal destruction of myelin, acute axonal damage/loss of axons and reactive astrogliosis in the white and grey matter. Myelin and oligodendrocytes are the main target of the inflammatory response, however the extent of remyelination as well as the loss or survival of mature oligodendrocytes and oligodendrocyte precursor cells varies between different disease stages as well as between white and grey matter. The present lecture focusses on the extent of remyelination in white and grey matter lesions in early and progressive disease stages. In addition, the pathology of mature oligodendrocytes as well as oligodendrocyte precursor cells is discussed. In general, remyelination is more extensive in grey than in white matter. Whereas mature oligodendrocytes are extensively present in early disease stages, they completely disappear in progressive MS. Oligodendrocyte precursor cells in contrast are still detectable in chronic lesions, however they fail to differentiate into myelinating cells. Preservation of oligodendrocytes is better in grey than white matter lesions and there is a clear age‐dependent decrease in the numbers of oligodendrocyte precursor cells. In summary, the major pathological differences between relapsing‐remitting and progressive multiple sclerosis related to oligodendrocyte pathology and remyelination are discussed.

S23‐3

Environmental control of astrocyte pathogenic activities in CNS inflammation

Francisco J. Quintana^1,2

¹Center for Neurologic Diseases, Harvard Medical School; ²The Broad Institute of Harvard and MIT

Astrocytes play important roles in the central nervous system (CNS) during health and disease. Thus, the identification of factors that regulate astrocyte activity may shed light on CNS physiology and guide new therapies for human neurologic disorders. In this class we will discuss mechanisms used by astrocytes to control CNS inflammation. In addition, we will discuss molecular pathways involved in the control of astrocyte function. For example, we recently found that microbial metabolites limit astrocyte pathogenic activities in the context of CNS inflammation. Specifically, metabolites of dietary tryptophan activate aryl hydrocarbon receptor (AHR) signaling in astrocytes to limit CNS inflammation and neurodegeneration. In addition, these metabolites also activate AHR on microglia to limit their intrinsic pathogenic activities and to modulate their ability to modulate astrocytic responses via the secretion of TGF‐alpha and VEGF‐B. Microglia‐derived TGF‐alpha acts via ErbB1 in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF‐B triggers FLT‐1 signaling in astrocytes and worsens EAE. VEGF‐B and TGF‐alpha also participate in the microglial control of human astrocytes. In summary, we identified novel positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a novel gut/brain pathway through which microbial metabolites limit pathogenic activities in microglia and astrocytes, suppressing CNS inflammation. This pathway may guide new therapies for MS and other neurologic disorders.

S23‐4

Up‐to‐date pathology in NMO

Izumi Kawachi

Department of Neurology, Brain Research Institute, Niigata University

This year marked the 150th anniversary of clinical description with pathological evidence of multiple sclerosis (MS) by Leopold Ordenstein (1835‐1902) and his mentor, Jean‐Martin Charcot (1825‐1893) in Paris (1868). They investigated the most comprehensive study on MS and Parkinson disease (PD) at that time, and represented a clear hallmark of MS in comparison with PD. Now, 150 years later, we have an increased knowledge of pathogenesis in MS and its related diseases. In particular, the discovery of aquaporin‐4 (AQP4) antibodies as a diagnostic biomarker of neuromyelitis optica (NMO) in 2005 is a landmark in the research history of MS and its related diseases. NMO is defined as ‘AQP4‐opathy’, because AQP4 autoantibodies and activated complements should target AQP4 water channels on astrocytes or ependymal cells in the CNS. On the other hands, MS is a disease primarily affecting myelin and oligodendrocytes, but the details of autoantigens have remained unclear. MS and NMO have distinct immunological and pathological features with different degrees of severity and pathogenetic mechanisms. The distinct inflammatory processes in these diseases may trigger cascades of events leading to disease‐specific or nonspecific neurodegeneration, via dysfunction or activation of astrocytes, oxidative burst activation in microglia/macrophages, mitochondrial damage and axonal energy failure, Wallerian degeneration and meningeal inflammation. The comparative consideration of ‘inflammation and neurodegeneration’ between MS and NMO will again highlight the most important issue, ‘what are the hallmarks of MS?’.

Special Lecture 5: SL5

The impact on diagnostic practice of current research into pediatric CNS tumors

David W. Ellison

Department of Pathology, St. Jude Children's Research Hospital

Many significant advances in our understanding of the genetic basis of pediatric CNS tumors have occurred in the last decade and have influenced the classification of disease and the way in which it is investigated and interpreted. Such advances are exemplified by the determination of medulloblastoma molecular groups, and with this and a few other examples as a foundation I will review how recent research findings are continuing to develop our view of these interesting tumors, impacting how we should classify them and test for clinicopathologically relevant molecular alterations.

Minisymposium 1: MS1

cIMPACT‐NOW: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy

Pieter Wesseling^1,2,3

¹Dept. of Pathology, Amsterdam Univ. Med. Ctrs/VUmc, Amsterdam, The Netherlands; ²Dept. of Pathology, Princess Maxima Ctr. for Ped. Oncol., Utrecht, The Netherlands; ³Dept. of Pathology, Univ. Med. Ctr. Utrecht, The Netherlands

The 2016 WHO Classification of CNS Tumours for the first time incorporates molecular characteristics in the definitions of some CNS neoplasms, allowing for a much more precise diagnosis, especially for diffuse gliomas and embryonal tumors. Meanwhile, further elucidation of the molecular underpinnings of these tumors and of the diagnostic/clinical relevance of these markers is occurring at a rapid pace. The cIMPACT‐NOW consortium, consisting of expert‐neuropathologists and a clinical advisory panel, was established in 2017 to facilitate incorporation of such novel, relevant molecular information. Since then, cIMPACT‐NOW has published recommendations regarding the terms ‘not otherwise specified’ (NOS) versus ‘not elsewhere classified’ in the context of CNS tumor diagnosis (cIMPACT update 1), and a clarification of the diagnosis of H3 K27M‐mutant gliomas and of diffuse low‐grade and anaplastic, IDH‐mutant astrocytomas (cIMPACT update 2). Furthermore, given that the traditional microscopic criteria for grading of diffuse gliomas are no longer sufficient, cIMPACT update 3 has proposed how EGFR amplification and/or combined gain of chromosome 7 and loss of chromosome 10 can be used to diagnose a histologically lower‐grade, diffuse, IDH‐wildtype astrocytoma as ‘molecular glioblastoma’. An ongoing effort is focussing on improved classification of pediatric low‐grade gliomas. The cIMPACT‐NOW consortium thus facilitates rapid and adequate implementation of novel molecular information in the diagnosis of CNS tumors and paves the way for improved future WHO classification of these neoplasms. (Contribution on behalf of the cIMPACT‐NOW Consortium; chair Dr. David N Louis).

Minisymposium 2: MS2

Sponsored by International Collaboration on Cancer Reporting (ICCR)
ICCR Datasets as Tools to Standardize and Improve Reporting of Pathology Information on CNS Tumors

Pieter Wesseling^1,2,3

¹Dept. of Pathology, Amsterdam Univ. Med. Ctrs/VUmc, Amsterdam, The Netherlands; ²Dept. of Pathology, Princess Maxima Ctr. for Ped. Oncol., Utrecht, The Netherlands; ³Dept. of Pathology, Univ. Med. Ctr. Utrecht, The Netherlands

Global standardization of pathology information on tumor classification, staging, prognostic and predictive information forms the basis for best practice in patient care and is a prerequisite for international epidemiological research and benchmarking. The International Collaboration on Cancer Reporting (ICCR; founded by major pathology organizations from around the world) produces validated and evidence‐based pathology datasets to improve cancer reporting internationally. Starting in 2017 and supported by the ICCR, a group of 15 experts (mainly neuropathologists) has produced three datasets with a consistent style and content on primary CNS tumors. The dataset “Final integrated report/diagnosis for CNS specimens” should be used in conjunction with the datasets “Histological assessment of CNS specimens” and “Molecular information for CNS specimens”. The backbone of these datasets is a set of CORE elements that (supported by level III‐2 evidence or unanimously agreed upon by the experts) are considered to be the minimum for adequate reporting of the tumor. In addition, the datasets include information on many NON‐CORE elements that were unanimously considered to be important as well. All pathology reports on CNS tumors should strive to render a diagnosis from the 2016 WHO Classification of CNS Tumours, preferably by using the layered approach described in the 2014 ISN‐Haarlem guidelines. It is expected that implementation of the ICCR datasets (which will be published on the ICCR website and as a journal article) will improve international reporting and benchmarking of CNS tumors. (Contribution on behalf of the ICCR CNS tumor expert committee; chair Dr. David N Louis)

Oral 10: O10‐1

Expression of GLUT1 on pseudopalisading cells and perivascular tumor cells: an independent prognostic factor of patients with glioblastomas

Satoru Komaki¹; Takuya Furuta¹; Kyouhei Yamada¹; Naohisa Miyagi²; Hideo Nakamura²; Motohiro Morioka²; Yasuo Sugita¹

¹Department of Pathology, Kurume University School of Medicine, Kurume, Japan; ²Department of Neurosurgery, Kurume University School of Medicine, Kurume, Japan

Glucose Transporter‐1 (GLUT1) is a 492‐amino‐acid membrane peptide and expressed in endothelial cells of blood brain barrier and a uniporter protein in humans encoded by the SLC2A1 gene. GLUT1 is essential for central nervous system because glial and neuronal cells are dependent on the energy source in glycometabolism. GLUT1 was expressed in various carcinomas and may play an important role in glycometabolism of malignant neoplasms. In order to clarify the role of GLUT1 in glioblastoma, the present study assessed the expression and localization of GLUT1 in consecutive 52 glioblastomas using immunohistochemical analysis and SLC2A mRNA using in situ hybridization. Immunohisochemically, GLUT1 expressed mainly expressed at the cell membrane of perivascular and pseudopalisading tumor cells. GLUT1 expression of cases divided into high expression group and low expression group as a result of immunohistochemical findings. All cases expressed GLUT1 in various degrees, and 16 (30.8%) cases showed strong intensity and high proportion of the tumor cells. SLC2A mRNA was also expressed more highly high expression group than low expression group. A Kaplan‐Meier survival analysis revealed that GLUT1 high expression group showed lower overall survival rate than low expression group (log‐rank test, p=0.001). MIB‐1 labeling index of GLUT1 high expression group was higher than that of low expression group. These results indicated that expression of GLUT1 in tumor cells enhance glycolysis and migration of glioblastomas and the correlation with the patient's prognosis.

O10‐2

Oncogene addiction switch from NOTCH to PI3K/AKT require simultaneous targeting of NOTCH and PI3K pathway inhibition in glioblastoma

Norihiko Saito; Kazuya Aoki; Nozomi Hirai; Ryo Suzuki; Satoshi Fujita; Kenichiro Sato; Haruo Nakayama; Morito Hayashi; Takatoshi Sakurai; Satoshi Iwabuchi

Department of Neurosurgery, Toho University Ohashi Medical Center

Notch signaling pathway regulates normal stem cells in the brain and glioma stem cells (GSCs). However, blocking the proteolytic activation of NOTCH with γ‐secretase inhibitors (GSIs) fails to alter the growth of some GSCs as GSIs seem to be active in only a fraction of GSCs lines with constitutive NOTCH activity. Here we report loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH to the phosphoinositol‐3 kinase (PI3K)/AKT pathway. We investigated the effects of Notch inhibition in GSC using GSI. Drug cytotoxicity test on 16 GSCs show differential growth response to GSI stratifying GSCs into two groups: responders (6 cell lines) vs non‐responders (10 cell lines). Active Notch signaling seems to be important features for the GSC as Notch inhibition only affected GSCs defined as having increased Notch activity. However in the responder group GSCs with the PTEN mutation seems to be less sensitive to GSI treatment. Here we show that NOTCH regulates the expression of PTEN and the activity of the PI3K/AKT signaling pathway in GSCs since treatment with GSI attenuated Notch signaling and increases PTEN expression. NOTCH regulates PTEN expression via Hes‐1 as knockdown of either Notch or Hes1 led to increase expression of PTEN.This novel observation suggests the need to simultaneous inhibition of both pathways as a means to improve therapeutic efficacy in human GBMs.

O10‐3

Development of a novel FISH probe for detection of 1p/19q codeletion in routine glioma diagnosis

Kaishi Satomi¹; Kai Yamasaki^2,3; Akihiko Yoshida¹; Susumu Wakai¹; Yuko Matsushita⁴; Yoshitaka Narita⁴; Takashi Komori⁵; Ryo Nishikawa⁶; Keisuke Ueki⁷; Koichi Ichimura²

¹Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; ²Division of Brain Tumour Translational Research, National Cancer Center Research Institute, Tokyo, Japan; ³Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan; ⁴Department of Neurosurgery and Neurooncology, National Cancer Center Hospital, Tokyo, Japan; ⁵Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ⁶Department of Neuro‐Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan; ⁷Department of Neurosurgery, Dokkyo University School of Medicine, Tochigi, Japan

The World Health Organization Classification of Tumours of the Central Nervous System (2016) has introduced integrated phenotypic and genotypic criteria to define diffuse glioma entities. Diagnosis of oligodendroglioma requires demonstration of 1p/19q codeletion. The analysis is commonly carried out using fluorescence in situ hybridisation (FISH). However, we need to be aware of potential methodological and interpretational pitfalls as some commercially available probes hybridise to loci at 1p36 or 19q13 and detect partial loss of these regions, which is a common feature of glioblastomas.To improve diagnostic accuracy of 1p/19q FISH, we have developed a novel FISH probe sets. They are designed to hybridise to 1p31 and 19q13.1, the loci rarely deleted in non‐oligodendroglial tumours. Ten diffuse glioma formalin‐fixed paraffin‐embedded (FFPE) samples (two oligodendrogliomas, three anaplastic oligodendrogliomas, one diffuse astrocytoma, and four anaplastic astrocytomas) were examined. The 1p/19q status of all samples was validated by multiplex ligation‐dependent probe amplification (MLPA) with corresponding frozen tissues. For FISH analysis, clear and bright target and control signals were detected in nine out of ten FFPE samples. Four oligodendroglial tumours lost a target signal yielded one red target signal and two green control signals. All astrocytic tumours showed balanced red and green signals. Our FISH results thus showed perfect concordance with the MLPA results and correctly identified 1p/19q codeleted tumors.Thus, we have successfully developed a novel FISH probe sets for detection of 1p/19q codeletion. A validation using a large number of various gliomas with known 1p/19q status determined by MLPA is underway.

O10‐4

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B‐cell lymphoma

Keishi Makino¹; Naoki Shinojima¹; Jun‐Ichiro Kuroda¹; Shigetoshi Yano¹; Yoshiki Mikami²; Akitake Mukasa¹

¹Department of Neurosurgery, Kumamoto University, Kumamoto, Japan; ²Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan

Purpose: Primary central nervous system diffuse large B‐cell lymphoma (CNS‐DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS‐DLBCL.

Methods: Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS‐DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients’ statuses for various markers, which were also evaluated for associations with survival outcomes.

Results: According to the Hans criteria, 26 patients (32.9%) had the germinal center B‐cell subtype and 53 patients (67.1%) had the activated B‐cell subtype. Forty‐one cases (51.9%) were positive for MYC (expression of over 40%), 33 cases (41.8%) were positive for BCL2 (expression of over 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B‐cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p=0.369) or progression‐free survival (p=0.253). However, BCL2 positivity was significantly associated with poor overall survival (p=0.039) and progression‐free survival (p=0.036). Co‐expression of MYC and BCL2 was not associated with survival.

Conclusion: Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS‐DLBCL.

O10‐5

Serum IL‐2 receptor and random skin biopsy for intravascular large B‐cell lymphoma ‐ cases with central nervous system involvement are particular for these diagnostic methods ? ‐

Eiichi Ishikawa¹; Erika Yamada¹; Rei Watanabe²; Hideaki Matsumura¹; Noriaki Sakamoto^1,3; Masahide Matsuda¹; Takao Tsurubuchi¹; Shingo Takano¹; Makoto Shibuya⁴; Akira Matsumura¹

¹Departments of Neurosurgery, Faculty of Medicine, University of Tsukuba; ²Departments of Dermatology, Faculty of Medicine, University of Tsukuba; ³Departments of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba; ⁴Central laboratory, Hachioji medical center, Tokyo medical university

Intravascular large B‐cell lymphoma (IVLBCL) is a rare type of extranodal B‐cell lymphoma which affects blood vessel lumina in all organs including brain. A number of researchers proved usefulness of random skin biopsy for diagnosis of IVLBCL. We retrospectively analyzed data of 21 patients with suspected IVLBCL (7 cases with central nervous system (CNS) involvement and 14 cases without CNS involvement) who underwent single or dual skin biopsies (5 cases) and random skin biopsies (16 cases). As a result, 16 cases including 6 CNS involvement cases out of 21 patients were diagnosed with IVLBCL. In 16 cases with random skin biopsy, the sensitivity, specificity and positive predictive value (PPV) of the random skin biopsy were 69.2%, 100% and 100%, respectively. In cases with data of both skin biopsies and plasma soluble interleukin‐2 receptor (sIL‐2R), there was significant correlation between tumor‐positive ratios of biopsy samples and sIL‐2R values. There was no difference in relationship of these diagnostic methods between CNS involvement and non‐involvement groups, although most of CNS involvement group had steroid use before diagnosis. In conclusion, the random skin biopsy should be applied for IVLBCL suspected patients before brain biopsy even in patients with CNS involvement, although this method has false‐negative result in low sIL‐2R cases especially steroid use.

Symposium 24: S24‐1

Prion and Prion disease: An overview and challenges

Hidehiro Mizusawa^1,2

¹National Center of Neurology and Psychiatry; ²Tokyo Medical and Dental University

Prion diseases are devastating neurodegenerative diseases in humans such as Creutzfeldt‐Jakob disease (CJD) and many animal species including sheep, cow, deer and cat. CJD presents rapidly progressive dementia and other symptoms resulting in 100 percent death usually in months without any medicine to treat. Most CJD cases are sporadic and of unknown origin. There are also genetic forms such as genetic CJD, Gerstmann‐Straeussler‐Scheinker syndrome and Fatal Familial Insomnia and, rarely, acquired forms including iatrogenic CJD such as due to human dura mater grafts or human pituitary derived hormones. Prion diseases are caused by conversion of normal prion proteins to transmissible (infective) abnormal prion proteins (prion). Three Nobel Prizes have been awarded in this narrow field of science but mechanisms of conversion, transmission and neuronal degeneration are far from elucidation. Fortunately the outbreak of variant CJD transmitted through foods contaminated with prion of bovine spongiform encephalopathy was almost eliminated but unfortunately mechanism of infection to young adults is unknown. Chronic wasting disease of deer spreading in north America, south Korea and recently in northern Europe appears an emerging threat to us. Recent studies on A‐beta, Tau, alpha‐synuclein and others linked to Alzheimer's disease, Parkinson's disease and so on demonstrated they also share characteristics with prion proteins, notably auto‐aggregation, self‐propagation and induction of lesions in animals. These findings suggest that research and development of treatment on Prion disease would contribute greatly to overcome such neurodegenerative diseases. International cooperation all over the world is crucial in overcoming Prion diseases.

Symposium 24: S24‐2

Neuropathology of prion diseases: principles and more

Gabor G. Kovacs

Institute of Neurology, Medical University of Vienna, Vienna, Austria

Prion diseases may be triggered through infection, germline mutations in PRNP, and most frequently by yet unidentified “sporadic” events that generate disease‐associated PrP. Classical light microscopic features of prion diseases include spongiform change, neuronal loss, and astro‐ and microgliosis. Amyloid plaques are seen only in a subset of prion diseases. Immunostaining for disease‐associated PrP reveals a wide range of morphologies from fine to coarse and plaque‐like deposits. The codon 129 polymorphism in combination with the Western blot pattern of PrPres serves as a basis for molecular subtyping of sporadic Creutzfeldt‐Jakob disease (CJD) and is important to distinguish the BSE‐related variant CJD characterized by florid plaques in neuropathology. Genetic prion diseases are associated either with parenchymal or vascular PrP amyloidosis, with CJD–like features, or with thalamic degeneration as in fatal familial insomnia, Furthermore, novel phenotypes, including the variably protease sensitive prionopathy or the PrP systemic amyloidosis, or yet unclassifiable forms such as the dementia with thalamic degeneration and peculiar cortical PrP immunoreactivity, have been also described. Studies on the intracellular processing and regional distribution patterns of disease‐associated PrP, or the description of concomitant proteinopathies in prion diseases contributed to the understanding of other neurodegenerative diseases. Interestingly, amyloid‐beta is mostly associated with iatrogenic CJD, tau pathology is more frequently seen in sporadic CJD and variant CJD, while genetic prion diseases show distinct combinations of additional proteinopathies including amyloid‐beta, tau, and alpha‐synuclein, but not TDP‐43. Thus, neuropathology still provides remarkable observations to unravel the secrets of prion diseases and those with prion‐like features.

S24‐3

What is abnormal prion protein (PrPSc)?

Atsushi Kobayashi

Graduate School of Veterinary Medicine, Hokkaido University

A conformational conversion of normal cellular isoform of prion protein (PrP^C) into abnormal misfolded isoform (PrP^Sc) is the central event in the pathogenesis of prion diseases. Although the structure of PrPC is well defined, the structure of PrP^Sc has resisted high‐resolution determination due to its insolubility and propensity to aggregation. Here, I summarize the current knowledge about the structure of PrP^Sc to shed light on the molecular mechanisms for the conformational conversion, neurotoxicity, and prion strain phenomena.

S24‐4

Neuropathology of V180I genetic CJD

Yasushi Iwasaki

Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Creutzfeldt‐Jakob disease (CJD) with causative point mutation of valine to isoleucine at codon 180 of prion protein (PrP) gene (V180I gCJD) is the most frequent form of gCJD in Japan, whereas this variant is extremely rare in Europe and North America. Previous reports on V180I gCJD have indicated the presence of extensive spongiform changes in the cerebral cortex and striatum and the absence of apparent cerebellar and brainstem lesions despite prolonged disease duration. Diffuse vacuoles in the cerebral cortex are observable macroscopically by loupe on the images of HE‐stained tissue. Gliosis, hypertrophic astrocytosis, and neuron loss are generally mild compared to those in sporadic CJD (sCJD) cases with prolonged disease duration in the cerebral cortex, despite the presence of innumerable vacuoles. The morphology of the vacuoles showed various‐sized and non‐confluent (VaSNoC) type. VaSNoC‐type vacuoles are visually different from the fine vacuoles observed in MM1‐type sCJD, as well as from the large confluent vacuoles observed in MM2‐cortical type sCJD. The appearance of VaSNoC‐type vacuoles in the cerebral cortex is considered a feature of V180I gCJD. The characteristic vacuoles show no expansion with disease progression. In addition, the dispersion of the major vacuole diameters is larger than that in the MM1‐type, and smaller than that in the MM2C‐type. The presence of VaSNoC‐type vacuoles in the cerebral neocortex of patients with CJD is useful for predicting V180I mutation prior to PrP gene analysis. With regard to prion protein immunostaining, very weak synaptic‐type deposition is recognized.

S24‐5

Neuropathology of FAP type prion disease

Kota Sato; Jingwei Shang; Mami Takemoto; Nozomi Hishikawa; Yasuyuki Ota; Koji Abe

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

Introduction: In most prion diseases, cognitive functions are commonly affected. However, a novel type of prion disease has recently been reported that is associated mainly with autonomic‐sensory polyneuropathy. We experienced two siblings (patient 1 and 2) who showed chronic progressive autonomic‐sensory polyneuropathy with novel PRNP gene mutation of c.534_535delCT(p.Asp178fs).

Results: Patient 1 showed urinary retention at age 26, then began to present orthostatic hypotension at age 30. After the age of 31, she suffered from frequent vomiting and diarrhea. At age 34, Her limbs presented thermoanesthesia and hypoalgesia, and her tendon reflexes showed generalized areflexia. Compound muscle action potentials and sensory action potentials were not evoked in bilateral tibial and sural nerves, respectively. Sural nerve biopsy revealed moderate loss of myelinated fibers with not amyloid material, but anti‐3F4 staining revealed ragged deposits. Cerebrospinal fluid levels of 14‐3‐3 and tau proteins were elevated. She suffered severe pneumonia and died at age 37. Her cerebral cortices showed severe spongiosis and neuropil degeneration. Anti‐3F4 staining showed coarse deposits in the cerebral cortex, the small vessels, and deposits in almost all other organs. Patient 2 began to suffer from frequent diarrhea at age 20, orthostatic hypotension at age 28, urinary retention at age 30, vomiting at age 32 and thermoanaesthesia at age 34. Similar to patient 1, anti‐3F4 staining in patient 2 revealed remarkable deposits of PrP in his sural nerve.

Conclusions: The present familial cases provide a very important suggestion for elucidating an exact mechanism of this particular prion disease.

Oral 11: O11‐1

Pathological spreading of TDP‐43 studied in real time: Impaired microglia function leads to propagation of TDP‐43 along the axon and into surrounding tissue

Adam J Svahn¹; Emily K Don¹; Rowan Radford¹; Nicholas J Cole¹; Albert Lee^1,2; Justin Yerbury³; Manuel B Graeber⁴; Roger S Chung¹; Marco Morsch¹

¹Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, NSW Australia; ²Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia; ³School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia; ⁴Brain Tumour Research Laboratories, Brain and Mind Centre, University of Sydney, Sydney, Australia

Introduction: TDP‐43 has been identified as the signature protein of the pathological inclusions that characterise amyotrophic lateral sclerosis (ALS/MND) and frontotemporal dementia (FTLD). The goal of this project was to evaluate whether microglia phagocytose TDP‐43 originating from dying motor neurons and whether such phagocytosis of TDP‐43 may be neuroprotective.

Methods: We examined the distribution and release of human (h)‐TDP‐43 in vivo in the zebrafish spinal cord in the presence and absence of microglia. We developed a technique (UV‐mediated neuronal injury) to selectively injure individual motor neurons expressing fluorescent hTDP‐43. We were able to observe the fate of TDP‐43 and the response of nearby microglia in real time at the single‐cell level. Antisense morpholino injections of pu1 allowed us to deplete the phagocyte population selectively.

Results: Following neuronal injury, we observed a reproducible pattern of neurodegeneration that results in cellular rupture and microglial clearance of TDP‐43. In contrast, when microglia were impaired, injured neurons showed a delayed demise characterized by cytoplasmic mislocalisation, somatofugal leakage and axonal spreading of TDP‐43. Furthermore, we occasionally observed TDP‐43 accumulation in surrounding tissue.

Conclusions: Our data provides novel insights into the mechanisms underlying TDP‐43 pathogenicity and suggest a protective role for microglia early on during neurodegeneration. It suggests that disruption of microglial uptake leads to cytoplasmic accumulation and spreading of TDP‐43. Thus, we propose that the pathological load of TDP‐43 in ALS/FTLD may be a direct consequence of microglial functional insufficiency, being unable to cope with the amount of neuronal debris that accumulates during disease progression.

O11‐2

Splicing Repression is a Major Function of TDP‐43 in Motor Neurons

Liam Chen; Philip Wong

Department of Pathology, Johns Hopkins Hospital

Nuclear depletion of TDP‐43, an RNA binding protein which represses aberrant splicing, may underlie neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). As multiple functions are ascribed to TDP‐43, its major role(s) that may be compromised in ALS/FTD remains unknown. Using Drosophila and murine models lacking TDP‐43 in motor neurons, we show that TDP‐43 mediated splicing repression is central to motor neuron physiology. Employing an AAV9 approach to deliver a chimeric protein comprised of the RNA recognition domain of TDP‐43 fused to an unrelated splicing repressor (RAVER1), we validate TDP‐43 splicing repression in the motor neuron as a therapeutic target. We establish that splicing repression is a principal role of TDP‐43 in motor neurons and identify a novel mechanism‐based therapeutic target for ALS.

O11‐3

HSF1 suppresses adenovirus‐induced neuronal TDP‐43 aggregate formation in culture

Kazuhiko Watabe¹; Yoichiro Kato²; Miho Sakuma³; Makiko Murata¹; Motoko Niida²; Akiyoshi Kakita⁴; Noriyuki Shibata²

¹Department of Medical Technology (Neuropathology), Kyorin University Facultty of Health Sciences; ²Department of Pathology, Tokyo Women's Medical University; ³School of Medicine, Tokyo Women's Medical University; ⁴Department of Pathology, Brain Research Institute, Niigata University

Introduction: TAR DNA‐binding protein 43 (TDP‐43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We have previously demonstrated neuronal cytoplasmic aggregate formation induced by recombinant adenoviruses expressing human wild type (WT) and C‐terminal fragment (CTF) TDP‐43 under the condition of proteasome inhibition in vitro and in vivo. In the present study, we examined whether heat shock response affects adenovirus‐induced TDP‐43 aggregate formation in vitro.

Methods: The 1464R rat neural stem cells were differentiated into neurons in the presence of retinoic acid, and co‐infected with adenoviruses expressing DsRed‐tagged human WT and CTF TDP‐43, and EGFP‐tagged human heat shock transcription factor 1 (HSF1), a master regulator of heat shock response, and candidate downstream heat shock proteins, i.e., heat shock protein 70 (HSP70), DNAJB2a/b, HSPB8, and HSPH3 in the presence of proteasome inhibitor MG‐132.

Results: Two days in vitro, DsRed‐positive, RIPA‐insoluble cytoplasmic aggregates containing phosphorylated TDP‐43 were formed in TDP‐43 adenovirus‐infected and MG‐132‐treated TuJ1‐positive neurons as revealed by immunofluorescence and western blot analysis. Co‐infection of HSF1 adenovirus markedly suppressed formation of the TDP‐43 aggregates. However, adenoviruses expressing HSP70, DNAJB2a/b HSPB8, and/or HSPH3 failed to suppress TDP‐43 aggregate formation.

Conclusion: These results suggest HSF1 as a potential therapeutic application for preventing TDP‐43 aggregate formation in ALS and FTLD. Further studies are required to identify candidate molecules, other than HSP70, DNAJB2a/b, HSPB8, and HSPH3, locating downstream of HSF1 to counteract TDP‐43 aggregate formation.

O11‐4

Early onset amyotrophic lateral sclerosis associated with a TARDBP S375G variant: neuropathologic characterization and neurobiologic studies

Kathy L Newell¹; Francesca Paron²; Jill Murrell³; Elisa Salis²; Cristiana Stuani²; Maurizio Romano⁴; Bernardino Ghetti³; Emanuele Buratti²

¹Dept of Pathology & Laboratory Medicine, University of Kansas School of Medicine, Kansas City, KS, US; ²International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; ³Dept of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, US; ⁴Dept of Life Sciences, University of Trieste, Trieste, Italy

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with usual onset in midlife. We are studying the brain and spinal cord from a 26 year‐old woman who developed clinical symptoms of ALS at age 22. A clinical history of ALS is reported in distant relatives. Histological sections were stained with Luxol fast blue‐H&E and immunohistochemically with TDP‐43 antibodies. Neuropathologic evaluation confirmed upper and lower motor neuron loss, corticospinal tract degeneration, and denervation atrophy of skeletal muscle. TDP‐43 immunoreactive neuronal and glial aggregates were present in motor cortex, globus pallidus, putamen, thalamus, substantia nigra, inferior olivary nucleus, and anterior horns. DNA analysis of the TARDBP gene identified a S375G change, predicted to affect post‐translational modification with elimination of a TDP‐43 protein phosphorylation site. A C9ORF72 expansion was not identified. The S375G variant was listed as low frequency in general population sequencing databases and reported in one 41 y/o patient with sporadic ALS. To determine whether this variant is pathogenic, we studied recombinant S375G protein in functional assays. In cultured cells, S375G expression was toxic, significantly more localized to the nucleus than wild‐type TDP‐43, and displayed significant increase in nuclear localization with respect to neighboring TDP‐43 mutations. A “phosphomimic” mutation, introduced to study the effect of loss of an endogenous TDP‐43 phosphorylation site, showed significantly altered TDP‐43 nuclear‐cytoplasmic distribution. This finding suggests an important pathophysiologic role for TDP‐43 phosphorylation in certain disorders. More studies of potentially pathogenic TDP‐43 variants, often reported in association with sporadic ALS or of unknown significance, are needed.

O11‐5

poly‐GR c9RANT correlate with neurodegeneration and clinicopathological phenotype in C9ORF patient

Nobutaka Sakae; Kevin F Bieniek; Yong‐Jie Zhang; Kelly Ross; Tania F Gendron; Melissa E Murray; Rosa Rademakers; Leonard Petrucelli; Dennis W Dickson

Department of Neuroscience, Mayo Clinic Jacksonville

Introduction: An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The pathomechanism of C9ORF72 pathology is unclear. Growing evidence from cell culture and animal model studies suggest the arginine containing poly‐PR and poly‐GR of the C9ORF72 repeat‐associated non‐ATG translated (C9RANT) dipeptide repeat polymers have distinct toxicity among the five C9RANTs. In human autopsy brain, however, the mechanism of poly‐GR toxicity is not fully understood.

Methods: We analyzed sense strand C9RANTs (poly‐GA, GP and GR) and asymmetric dimethyl arginine (aDMA) pathology in brains of 40 patients with C9ORF72 mutation using unbiased digital image analysis. We also studied overexpression of GFP‐tagged C9RANTs in HEK293 cells.

Results: The burden of poly‐GR neuronal cytoplasmic inclusion (NCI) was associated with neurodegeneration and c9FTLD/MND subtype in hippocampus and frontal cortex. Further, aDMA pathology was correlated with poly‐GR NCI and preferentially co‐locarized with poly‐GR NCI. The in vitro studies suggested that aDMA modification of poly‐GR contributes to formation of poly‐GR cytoplasmic inclusions and gain of toxicity of poly‐GR.

Conclusion: We found that poly‐GR NCI burden correlates with neurodegeneration in C9FTLD/MND patients. The distribution of poly‐GR NCI and aDMA NCI were highly correlated. Neuropathological studies and in vitro assays suggested that gain of toxicity of poly‐GR might be associated with aDMA modification. Our study provides novel insights into the contribution of poly‐GR toxicity towards neurodegeneration of C9FTLD/MND.

O11‐6

An autopsy case of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN‐P, or HMSN Okinawa type)

Shugo Suwazono^1,2; Tomoyasu Matsubara³; Ryo Nakachi²; Eriko Atsumi⁴; Yuishin Izumi⁵; Miwako Kido²; Takashi Tokashiki²; Ryuuji Kaji⁵; Mari Yoshida⁶; Shigeo Murayama³

¹Center for Clinical Neuroscience, National Hospital Organization Okinawa Hospital; ²Department of Neurology, National Hospital Organization Okinawa Hospital; ³Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; ⁴Department of Pathology, National Hospital Organization Okinawa Hospital; ⁵Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School; ⁶Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN Okinawa type; HMSNO, OMIM # 604484, or HMSN‐P, as used in the first detailed report [Takashima, 1997]), is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, and slowly progressive course [Fujisaki, 2018]; it is associated with a mutation in TRK‐fused gene (TFG) [Ishiura, 2012]. This disease might serve as a good example for considerations of the pathomechanisms of neurodegenerative disorders whose proposed etiologies are caused by one gene mutation; therefore, detailed pathological examination is very important.

Clinical summary: The patient exhibited painful muscle cramps and weakness of the lower extremities at the age of 44; this lower extremity weakness gradually worsened, such that, fifteen years later, she was unable to walk and was admitted to our hospital. Prominent fasciculations on all extremities, proximal dominant muscle weakness, and mild superficial sensory impairment were observed; deep tendon reflexes were diminished and no pathological reflexes were present. Non‐invasive positive pressure ventilation was initiated at the age of 70; tracheostomy was performed at the age of 74. Gastrostomy was implemented at the age of 80; the patient died at the age of 80, due to sepsis following pneumonia.

Pathological findings: Upper and lower motor neuron analysis showed cellular loss. Anti‐TFG antibody and anti‐phosphorylated TDP‐43 antibody staining revealed positive intracellular granules.

Conclusion: Pathological findings in this case confirmed the characteristic findings reported in HMSN‐P previously [Takashima, 1997, Fujita, 2011].

Symposium 25: S25‐1

Rare brain tumor diagnosis: reassessment in the era of methylation profiling

David Capper^1,2

¹Institute of Neuropathology, Charité‐Universitätsmedizin Berlin, Germany; ²German Cancer Consortium (DKTK), Partner Site Berlin/German Cancer Research Center (DKFZ), Heidelberg, Germany

Genome‐wide DNA methylation profiling is evolving as a promising tool for brain tumor classification and the identification of new biological tumor classes. In this presentation, the possibilities to refine the diagnosis of several rare brain tumors such as anaplastic pilocytic astrocytoma, diffuse leptomeningeal glioneuronal tumor, olfactory neuroblastoma, astroblastoma and isomorphic astrocytoma will be presented. Further, more general technical aspects of DNA methylation profiling will be discussed as well as possible future developments in the field of rare brain tumors.

S25‐2

Exosomal miRNAs as blood‐based biomarkers in glioblastoma

Michael E Buckland^1,2

¹Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, Australia; ²Brain & Mind Centre, University of Sydney, Sydney, Australia

Introduction: There is growing interest in ‘liquid biopsies’ in cancer diagnosis and management. Commonly used assays include cell free DNA and ‘free circulating’ RNA such as microRNA (miRNA). Exosomes are nano‐sized extracellular vesicles released by many cells that contain a distinct molecular cargo, including miRNA and DNA. Exosomes released by glioblastoma cross the blood‐brain‐barrier and can be detected in the peripheral circulation.

Methods: Serum exosomal‐miRNAs were isolated from glioblastoma (n=12) patients and analysed using unbiased deep sequencing. Results were compared to sera from age‐ and gender‐matched healthy controls, and to grades II‐III (n=10) IDH‐mutant glioma patients. Additional sera from glioblastoma patients (n=4) and independent sets of healthy (n=9) and non‐glioma (n=10) controls were used to further test the specificity and predictive power of this exosomal‐miRNA signature.

Results: Twenty‐six miRNAs were differentially expressed in serum exosomes from glioblastoma patients relative to healthy controls. Random forest modelling and data partitioning selected seven miRNAs as the most stable for classifying glioblastoma. Within this model, two iterations of these miRNA classifiers could distinguish glioblastoma patients from controls with perfect accuracy. The seven miRNA panel was able to correctly classify all specimens in validation cohorts (n=23). Also identified were 23 dysregulated miRNAs in to grades II‐III (n=10) glioma patients; a partially overlapping yet distinct signature of lower grade glioma.

Conclusions: This preliminary study demonstrates a strong signal of glioblastoma in peripheral blood exosomal miRNA. Longitudinal studies of larger patient populations are underway to determine the clinical utility of these assays.

S25‐3

Brain region specific molecular profile of cerebellar gliomas

Masashi Nomura^1,2; Akitake Mukasa³; Shota Tanaka¹; Yoshitaka Narita⁴; Motoo Nagane⁵; Keisuke Ueki⁶; Ryo Nishikawa⁷; Junji Shibahara⁸; Hiroyuki Aburatani²; Nobuhito Saito¹

¹Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo; ²Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo; ³Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University; ⁴Department of Neurosurgery and Neuro‐Oncology, National Cancer Center Hospital; ⁵Department of Neurosurgery, Kyorin University Faculty of Medicine; ⁶Department of Neurosurgery, Dokkyo Medical University; ⁷Department of Neuro‐Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University; ⁸Department of Pathology, Kyorin University Faculty of Medicine

Recent profiling efforts of gliomas have demonstrated different alterations among patient's age groups and originated brain regions. For example, H3K27M mutation, which disrupts epigenetic regulation globally and leads to tumorigenesis, occurs frequently in pediatric midline gliomas. These specific profiles have been suspected to be associated with glial and neuronal development. In this study, we analyzed cerebellar gliomas, which have not been studied enough, using whole‐exome sequencing (17 cases), RNA‐sequencing (14 cases), and methylation array (17 cases). The genomic analysis revealed frequent mutations in chromatin‐regulation genes and p53‐related genes. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. Methylation and expression analyses combined with data of 315 gliomas originated from each anatomical region identified different regulation of transcription factor genes including SOX10, OLIG1/2 and FOXG1, which play an important role in normal developmental programs of central nervous system, reflecting distinct cellular‐origin of gliomas at each anatomical region. The pattern of cerebellar gliomas was close to that of oligodendrocyte precursor cell lineage. These findings suggested regional specificity of gliomas and may provide potential of tailored targeted therapy for gliomas according to the cellular‐origin.

S25‐4

Identification of the therapeutic targets for brain tumor‐related fusion genes using an animal model

Tatsuya Ozawa¹; Syuzo Kaneko²; Mutsumi Takadera¹; Zhiwei Qiao³; Frank Szulzewsky⁴; Tadashi Kondo³; Eric C. Holland⁴; Ryuji Hamamoto²; Koichi Ichimura¹

¹Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Japan; ²Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Japan; ³Division of Rare Cancer Research, National Cancer Center Research Institute, Japan; ⁴Division of Human Biology, Fred Hutchinson Cancer Research Center, Washington, USA

Fusion genes provide therapeutic insight as the breakpoints highlight cancer‐relevant genes. In contrast to druggable kinase fusions, it is not easy to identify the therapeutic targets for ones composed of an unpredictable domain such as a transcription factor, thus likely necessary to examine the molecular function in detail. The genetically engineered mouse model is an essential tool for current cancer research but has the critical drawback which cannot perfectly reproduce the complex molecular heterogeneity of human cancers because a limited number of genes is enough to induce tumors in mice. However, given the potential driver function of the fusions, the model appears to fit for their functional analysis. So far, we have presented that the C11orf95‐RELA fusion, recently identified in ependymomas (EPNs) was a potent oncogene capable of inducing human EPN‐like tumors in an RCAS/tv‐a retroviral gene transfer system. In this talk, we would demonstrate to explore for the therapeutic targets of the C11orf95‐RELA fusion through the functional analyses and drug screening with our EPN model, and then the application of our experimental approach to other brain tumor‐related fusions to identify the therapeutic targets.

S25‐5

Clinical results of patients with lower grade gliomas in our institute and surgical strategy using intraoperative molecular diagnosis

Masayuki Nitta^1,2; Yoshihiro Muragaki^1,2; Takashi Maruyama^1,2; Taiichi Saito¹; Shunsuke Tsuzuki¹; Shunichi Koriyama¹; Takashi Komori³; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University; ²Faculty of Advanced Techno‐Surgery (FATS), Institute of Advanced Biomedical Engineering & Science Graduate School of Medicine, Tokyo Women's Medical University; ³Department of Pathology, Tokyo Metropolitan Neurological Hospital

Introduction: In the 2016 WHO classification, genetic information was introduced in the pathology diagnosis of gliomas, and the correlation between genotype and prognosis has been shown. Correlation between extent of removal (EOR) and prognosis has been shown, but it is often difficult to achieve both high EOR and preservation of brain function. Here, we report the clinical results of lower grade gliomas (LGGs) in the WHO new classification at our facility and discuss the significance of the surgical strategy based on intraoperative rapid molecular diagnosis that our institution is working on.

Methods: In 366 cases (G2 219 cases, G3 147 cases) with newly diagnosed LGGs that could be classified according to 2016 WHO classification in our hospital (2004‐2014), the relation between the EOR and prognosis was retrospectively analyzed. Accuracy of intraoperative rapid molecular diagnosis of IDH mutation and 1p/19q codeletion using HRM method and p53 /ATRX immunostaining was evaluated.

Result: The 10‐year survival rate of oligodendroglioma was 88% in G2 (121 cases), 80% in G3 (59 cases), the 10‐year survival rate of DA‐IDH mutant was 63% in G2 (66 cases), MST of G3 (46 cases) was 13.6 years, MST of DA ‐ IDH wild‐type was G2 (32 cases) 12.6 years, G3 (42 cases) 3.9 years. The EOR correlated with prognosis in DA‐IDH wild‐type G2.

Conclusion: In the LGGs, the prognosis and the significance of EOR was significantly different between subtypes. Rapid intraoperative molecular diagnosis seems to be useful for determining the removal strategy in lower grade glioma surgery.

Oral 12: O12‐1

Novel patient‐derived primary central nervous system lymphoma xenograft models to exploit therapeutic target

Yohei Miyake¹; Kensuke Tateishi¹; Taishi Nakamura¹; Akio Miyake²; Yuko Matsushita³; Hidetoshi Murata¹; Shoji Yamanaka²; Tetsuya Yamamoto¹; Koichi Ichimura³

¹Department of Neurosurgery, Yokohama City University, Yokohama, Japan; ²Department of Pathology, Yokohama City University, Yokohama, Japan; ³Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan

Introduction: The large‐scaled gene analyses revealed that chronic activation of NF‐kB signaling pathway, mainly caused by CD79B or MYD88 mutation, played a crucial role on tumorgenesis of primary central nervous system lymphoma (PCNSL). Recently, several targeting drugs for the NF‐kB signaling pathway, such as ibrutinib (BTK inhibitor), have been discovered. To elucidate the molecular and biological mechanism of PCNSL, highly‐reproducible animal models is important. However, the establishment of PCNSL animal models is considered to be difficult, because little patient‐derived PCNSL cell lines have been reported. In this study, we attempted to establish patient‐derived PCNSL cell line based on our experiences to create glioblastoma stem like tumorsphere models.

Method: After surgical biopsy, PCNSL cells were implanted to the immunodeficient mice brain. Once tumor was harvested, pathological and genetic analyses were performed to confirm their reproducibility between patient specimens and patient‐derived cell lines.

Results: Of note, we successfully established 7 xenograft models (patient‐derived PCNSL cell lines) out of 9 cases. In all 7 cases similar pathological characteristics was observed. Immunohistochemical analysis demonstrated positive expression of of B‐cell markers, including CD20 and CD79a. DNA fingerprinting revealed matched DNA identification.Besides, we confirmed CD79B and MYD88 mutation were completely inherited to the cell lines. Sensitivity of ibrutinib and methotrexate were variable in each cell line. Currently, we are performing the comprehensive genome analysis using the target sequence panel.

Conclusion: We established the largest panels of patient‐derived PCNSL xenograft models, which would develop future preclinical investigations.

O12‐2

Clinicopathological study of diffuse large B‐cell lymphoma associated with chronic inflammation arising in the CNS

Yasuo Sugita; Takuya Furuta; Satoru Komaki; Hiroko Muta; Mayuko Moritsubo; Kouichi Ohshima

Department of Pathology, University of Kurume, Kurume, Japan

Introduction: Diffuse large B‐cell lymphoma associated with chronic inflammation (DLBCL‐CI) is a lymphoma occurring in the setting of longstanding chronic inflammation and showing association with EBV. DLBCL‐CI involving the CNS is, however, rare, and the features are not well characterized.

Methods: We assessed clinicopathological features of 4 DLBCL‐CI cases.

Clinical results: MRIs showed a solid and a cystic lesion (case 1, 66 yr, female), or a cystic lesion in the posterior fossa (case 2, 57 yr, female), respectively and a left frontal (case 3, 96 yr, male), or a right frontal‐temporal (case 4, 77 yr male), subdural lesion, respectively. Aggressive clinical courses were recorded in cases 1 and 3, and 2 patients remained in remission (cases 2, 4), respectively.

Pathological results: In case 1, the solid lesion showed a proliferation of atypical lymphocytes, and the cystic lesion showed keratinous debris, which was consistent with an epidermoid cyst (EC). In case 2, the cystic lesion was consistent with an EC. Additionaly, atypical lymphocytes were scattered adjacent to an EC without forming a mass. In case 3, atypical lymphocytes conglomerated in the thick outer membrane (TOM) and subdural space of chronic subdural hematoma (CSH) and invaded brain parenchyma. In case 4, atypical lymphocytes conglomerated in only TOM of CSH. In all cases, atypical cells were EBV positive and in the fibrin background.

Discussion: Fibrin‐associated EBV‐positive DLBCL (FDLBCL) has been reported as the variant of DLBCL‐CI with favorable prognosis. Therefore, cases 2, 4 might be consistent with FDLBCL of the CNS.

O12‐3

HMGA2 is a prognostic factor associated with malignant phenotype in medulloblastoma

Arakawa Yoshiki; Bin Liu; Yukinori Terada; Yasuzumi Matsui; Etsuko Hattori; Sosuke Sumiyoshi; Nobuyuki Fukui; Masahiro Tanji; Yohei Mineharu; Susumu Miyamoto

Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

Medulloblastoma is the most common of the embryonal tumor arising in the cerebellum. The molecur mechanism of its oncogenesis has been revealed by recent studies. The constitutive expression of high mobility group AT‐hook 2 (HMGA2) is associated with a highly malignant phenotype and reduced survival in several malignancies. However, little is known about the clinical and biological significance of HMGA2 in medulloblastoma. In this study, we explore the expression, prognostic and therapeutic role of HMGA2 in medulloblastoma. HMGA1 and HMGA2 expressions were examined using immunohistochemistry in 20 patients with medulloblastoma. To examine the function of HMGA2 expression, knock‐down HMGA2 expression was applied in Daoy, D283 and D341 cells. Overexpressions of HMGA1 and HMGA2 were frequently identified in medulloblastoma tissues. In addition, high expression of HMGA2 correlated with high proliferation marker Ki‐67 labeling index. High expression of HMGA2 was signifficantly associated with progression free survivail and overall survival of patients with medulloblastoma (p=0.021 and p=0.016, respectively). Functional experiments confirmed that knock‐down of HMGA2 resulted in inhibited cell proliferation, migration/invasion and enhanced apoptosis in vitro. In conclusion, HMGA2 overexpression is frequent in medulloblastoma, and its expression is related to proliferation marker and poor prognosis.

O12‐4

The correlation of fluorescence of protoporphyrinogen 9 and molecular biological characters in gliomas

Shigeo Ohba¹; Kazuhiro Murayama²; Syunsuke Nakae¹; Eriel Sandika³; Yuya Nishiyama¹; Hikaru Sasaki³; Seiji Yamada⁴; Masato Abe⁵; Mitsuhiro Hasegawa¹; Yuichi Hirose¹

¹Department of Neurosurgery, Fujita Health University; ²Department of Radiology, Fujita Health University; ³Department of Neurosurgery, Keio University; ⁴Department of Pathology, Fujita Health University; ⁵Department of Pathology, School of Health Sciences, Fujita Health University

To increase the extent of resection of gliomas, several methods such as use of 5‐aminolevulinic acid (5‐ALA) have been performed. The correlation of intraoperative fluorescence and several clinical, radiographies, molecular biological and histopathological characters were evaluated. Total 104 patients of gliomas, including 53 males and 51 females were evaluated. The mean age was 54.2 years. Intraoperative fluorescence was observed in 78.8% of cases. Older age, enhanced cases, and high CBV were revealed to be associated with intraoperative fluorescence. The rate of intraoperative fluorescence in World Health Organization (WHO) grade 2, 3, and 4 tumors was 26.3%, 76.9%, and 96.6%, respectively. The MIB‐1 index in the tumor with intraoperative fluorescence was significantly higher than in non‐fluorescence tumors. The positive rate of intraoperative fluorescence in gliomas harboring wildtype isocitrate dehydrogenase (IDH) is significant higher than that in gliomas harboring mutant IDH. Limited to WHO grade 2 and 3 tumors, the positive rate of intraoperative fluorescence in gliomas harboring wildtype IDH tumors tend to be higher than that in gliomas harboring mutant IDH. In vitro assay revealed that artificial glioma cells transformed by mutant IDH showed less amount of exogenous 5‐ALA derived protoporphyrinogen 9(Pp9) compared to artificial glioma cells transformed by H‐Ras. There was the difference in the expression of mRNA of enzymes associated with the metabolites of 5‐ALA between them. These results suggested that mutant IDH affected the amount of Pp9 indirectly, which contributed to the less intraoperative fluorescence in gliomas harboring mutant IDH compared to gliomas without mutant IDH.

O12‐5

Clinical features of supratentorial cortical ependymomas: a report of 8 cases at a single center

Yuji Matsumoto¹; Tomotsugu Ichikawa^1,2; Kazuhiko Kurozumi¹; Yasuhiko Hattori¹; Yusuke Tomita¹; Toshihiko Shimizu¹; Yoshihiro Otani^1,3; Kentaro Fujii¹; Hiroyuki Yanai⁴; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Okayama, Japan; ²Department of Neurosurgery, Kagawa Prefectural Central Hospital, Kagawa, Japan; ³Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA; ⁴Department of Pathology, Okayama University Hospital, Okayama, Japan

Objective: Supratentorial cortical ependymomas (CEs) are rare. These lesions, selectively occurring in the superficial cortex, are not fully characterized. We herein summarize our experience with CEs.

Methods: The study population comprised 8 patients from our institution from January 1980 to April 2018. We retrospectively reviewed their clinical characteristics, imaging findings, treatment methods, pathological features, and clinical outcomes.

Results: The median age at diagnosis was 7.5 years. The 2 most common clinical manifestations were intracranial hypertension (n=3, 38%) and seizures (n=3, 38%). The tumors were located in the frontal lobe (n=4, 50%), parietal lobe (n=4, 50%). The mean tumor diameter was 70 mm. All tumors had a cystic appearance, and calcification was observed in 6 cases (75%). All patients underwent surgical resection. Gross total resection was achieved in 6 cases (75%), and subtotal resection was performed in 2 cases (25%). Seven tumors (88%) qualified as WHO grade III, and 1 tumor (12%) qualified as WHO grade II. Six tumors (75%) showed immunopositivity for L1CAM. Postoperative radiotherapy was performed for all patients with grade III tumors except children aged <3 years. Although 4 patients (50%) developed recurrence after the initial treatment, all were alive throughout the follow‐up period.

Conclusions: Although most CEs are grade III and positive for L1CAM, which is a poor prognostic marker in supratentorial ependymomas, all patients showed a good prognosis. Gross total resection and adjuvant radiotherapy contribute to a relatively favorable prognosis of CEs compared with other supratentorial ependymomas.

Oral 13: O13‐1

The neuropathology of motor subtypes of Parkinson's disease: from the brainstem to basal ganglia

Bension S Tilley¹; Marc H Goldfinger¹; Ronald KB Pearce²; Steve M Gentleman¹

¹Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London; ²Charing Cross Hospital, Imperial College Healthcare NHS Trust

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder with two main motor presentations: tremor‐dominant (TD) and akinetic‐rigid (AR). Previous studies of the neuropathology of subtypes have focused on the substantia nigra (SN) and locus coeruleus (LC), finding more degeneration in AR cases. However, these studies used H&E sections that do not allow for accurate demarcation of the SN from neighbouring pigmented nuclei. We have created a novel midbrain atlas using immunohistochemistry that accurately isolates the SN. SN neurons modulate the activity of striatal cholinergic interneurons (ChIs) which are dysregulated in PD and there is evidence of differential cholinergic tone in motor subtypes.

Methods: 40 TD and 40 AR‐presenting cases were selected from the Parkinson's UK Tissue Bank. Sectuibs from the midbrain and pons were immunostained for tyrosine‐hydroxylase, α‐synuclein, tau, amyloid‐β and choline‐acetyltransferase (ChAT) for basal ganglia sections. Based on our midbrain atlas, TH‐neuron counts in the SN and LC were performed and ChI arborisation assessed in the striatum. Pathology was quantified using a %‐coverage methodology.

Results: There were no significant differences between PD motor subtypes in SN or LC TH‐neuron counts. There was significantly more LC α‐synuclein pathology in AR cases compared to TD. A reduction in primary and secondary arborisation was seen in striatal ChIs of AR cases compared to TD.

Conclusions: We have shown, in contrast to previous studies, that motor subtypes are likely to be non‐monoaminergic in their origins, perhaps reflecting differences in cholinergic tone in the striatum and other brain regions.

O13‐2

The accumulation of tyrosine hydroxylase to Lewy bodies in PLA2G6 associated neurodegeneration

Hisae Sumi‐Akamaru^1,2; Yasuo Miki³; Yuichi Riku^4,5,6; Shinsuke Kato⁷; Koichi Wakabayashi³; Mari Yoshida⁵; Hideki Mochizuki²

¹Department of Clinical Laboratory, Higashi‐Osaka Medical Center; ²Department of Neurology, Graduate School of Medicine, Osaka University; ³Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine; ⁴Department of Neurology, Nagoya University Graduate School of Medicine; ⁵Institute for Medical Science of Aging, Aichi Medical University; ⁶Laboratoire de Neuropathologie, Groupe Hospitalier PITIE‐SALPETRIERE; ⁷Division of Neuropathology, Department of Brain and Neurosciences, Tottori University Faculty of Medicin

Introduction: Tyrosine hydroxylase (TH), a rate‐limiting enzyme of catecholamine synthesis, binds to phospholipid membranes, like a‐synuclein (aSyn). Recently, we reported that aSyn accumulates to the degenerated mitochondria both in the disease models and the patient with PLA2G6 dysfunction, in which the phospholipid metabolism is abnormal. To clarify the mechanism of aSyn accumulation in PLA2G6 associated neurodegeneration (PLAN), we analyzed the expression of TH in Lewy bodies.

Methods: The expression of TH was quantitatively estimated in nigral neurons of PLAN (n=2, age 20, 48; duration 17, 23years) and sporadic Parkinson disease (sPD, n=7, average age 77; average duration 14). In the double immunohistochemistry against TH and phosphorylated aSyn, the colocalization rate was calculated in the Lewy bodies or pre‐inclusions.

Results: In PLAN, the TH expression in the neuronal cytoplasm was well preserved. The expression of TH was observed also on the surface of Lewy bodies and pre‐inclusions, similarly to the localization of the mitochondrial marker protein. The rate of the colocalization was 90% and 83% in the neuronal inclusions of each PLAN case, respectively. In sPD, the expression of TH was observed diffusely in the halo of Lewy bodies. The colocalization was 27% of the total neuronal inclusions including Lewy bodies and pre‐inclusions.

Conclusions: The high expression of TH in Lewy bodies would be associated with the preserved expression of TH in the neurons of PLAN. The accumulation of TH on the surface of Lewy bodies might suggest that TH binds to the phospholipid membranes.

O13‐3

A new MSA model mice recapitulate some pathological and clinical features in human patients

Kunikazu Tanji¹; Yasuo Miki¹; Fumiaki Mori^1,2; Yoshikazu Nikaido²; Hidemi Narita^1,3; Akiyoshi Kakita⁴; Hitoshi Tkahashi⁵; Koichi Wakabayashi¹

¹Department Neuropathology, Hirosaki University School of Medicine; ²Department Anesthesiology, Hirosaki University School of Medicine; ³Department Rehabilitation Science, Hirosaki University of Health and Welfare; ⁴Department Pathology Neuroscience, Brain Research Institute, University of Niigata; ⁵Department Pathology, Brain Research Institute, University of Niigata

Introduction: Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder characterized clinically characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Despite extensive research, the mechanism underlying disease progression in MSA remains unknown. Animal models of human diseases that recapitulate clinical, biochemical and pathological features are indispensable for understanding molecular mechanisms and advancing preclinical studies. However, model animals for MSA have been limited so far. Importantly, considering that MSA is an adult‐onset disease, it would be more suitable that model animals manifest abnormal protein aggregates from adulthood.

Objective: To examine pathophysiological mechanism underlying MSA progression, we generated MSA model mice using Cre‐loxp technique to express inducible alpha‐synuclein, which is a major component of pathological hallmarks of MSA.

Results: From adulthood, our MSA mice showed that excessive alpha‐synuclein expression in oligodendrocytes, resulted in abnormal alpha‐synuclein accumulation and modifications similar to human MSA pathology. Also MSA mice exhibited a part of MSA‐clinical features such as lower motor activity and sudden death.

Conclusion: These findings suggest that new MSA model mice would be useful to analyze the pathophysiological alteration underlying its disease progression.

Symposium 26: S26‐1

Genome‐wide DNA methylation profiling reveals molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma

Taishi Nakamura¹; Koichi Ichimura²

¹Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; ²Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan

Anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity in the revised WHO classification 2016. Furthermore, some anaplastic PXAs were reported extremely poor prognosis, which showed a similar molecular profiles to pediatric glioblastomas (GBMs). Recent integrated molecular classification for primary CNS tumors proposed some discrepant separations between histological feature and that of molecular. Herein we present an extreme aggressive anaplastic PXA which housed pediatric GBM molecular profile in genome‐wide molecular analysis. A full implementation of molecular approach is the key to predict prognosis and determine treatment strategy for anaplastic PXAs.

S26‐2

The diversity of pediatric high grade gliomas

Akihide Kondo¹; Atsushi Arakawa²; Mario Suzuki¹; Osamu Akiyama¹; Hajime Arai¹

¹The department of neurosurgery, Juntendo University, Tokyo, Japan, The department of human body pathology, Juntendo University, Tokyo, Japan

Background: The high‐grade glioma in children is biologically diverse in the form of molecular biology . Even in the classification in 2016, it is difficult to say we have a comprehensive idea about these tumors. Since a new entity appeared in it.

In recent reports, depending on the onset age, the molecular biological factor is different even if the morphology is similar. It has been also reported that the treatment prognosis is various depending on their molecular characters.

Patients: We encountered the kids suffering from high‐grade gliomas who had a surgery in our institution. We examined tumor specimens obtained from the surgeries.

Results: Clinical course and specimen analysis of six cases were possible. The ages were from 0 to 13 years old, and all were diagnosed as high‐grade glioma in morphologically. In five cases, we carried out molecular biological analysis.

Conclusion: The prognosis and the tumor characteristics were examined by age. By comparing the facts those had been reported with our pathological image and the molecular biological factors, specific trend could be seen in our series.

S26‐3

Clinicopathological features of pediatric supratentorial high grade glioma

Koji Yoshimoto¹; Hiroyuki Uchida¹; Hajime Yonezawa¹; Nobuhiro Hata²; Masahiro Mizoguchi²; Hirofumi Hirano¹

¹Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan; ²Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Objective: Pediatric supratentorial high grade glioma includes various histological type of tumors. Since the introduction of new diagnostic criteria Diffuse midline glioma, H3 K27M‐mutant in WHO 2016 classification, we need to integrate the pathological diagnosis and molecular diagnosis. In this study, we aim to retrospectively analyze the clinicopathological features of pediatric supratentorial high grade glioma.

Materials and methods: We collected 20 pediatric supratentorial high grade glioma cases which were operated as initial surgery during the period after 2000 in the two institutions to which first author belong. Patient age ranged from 3 to 20 years old (median 11y). Main tumor locations were as follows: thalamus/basal ganglia, 10cases; frontal lobe and parietal lobe, 4cases, respectively; temporal lobe, 2cases. DNA‐based or immunohistochemical analysis to detect H3F3A mutations were performed in 12 cases out of total 20 cases.

Results: Histopatholgical diagnosis based on WHO 2007 criteria was glioblastoma 13 cases, astroblastoma 3 cases, anaplastic ependymoma 2 cases, anaplastic astrocytoma 1 case, PNET 1 case. K27M mutations were detected in 6/10 glioblastoma, and one case of anaplastic ependymoma, whereas two cases of glioblastoma and a astroblastoma were G34R mutation. Accordingly, 7 cases out of 12 cases can be diagnosed as Diffuse midline glioma, H3 K27M‐mutant.

Conclusions: Diffuse midline glioma, H3 K27M‐mutant occurs in the midline region, and include not only astrocytic high grade tumors but also other morphological tumors.

FranzNissl Young Investigator Award Lecture: NA

Pathological epidemiology of chronic traumatic encephalopathy in Southeastern Minnesota, U.S.A.

Kevin F. Bieniek¹; Melissa M. Blessing²; Amanda M. Serie¹; Michael A. Paolini II²; Melissa E. Murray¹; Rodolfo Savica^3,4; R. Ross Reichard²; Dennis W. Dickson¹

¹Department of Neuroscience, Mayo Clinic; ²Department of Laboratory Medicine and Pathology, Mayo Clinic; ³Department of Neurology, Mayo Clinic; ⁴Department of Health Sciences Research, Mayo Clinic

Introduction: Traumatic brain injury (TBI) is a strong environmental risk factor for the development of dementia. TBI‐dementia risk has been reported to be dose‐dependent based on TBI severity and number of TBI. Pathologically, single‐incident TBI can lead to hypoxic‐ischemic injury, inflammation, and axonal injury whereas repetitive TBI can result in a progressive neurodegenerative disorder known as chronic traumatic encephalopathy (CTE). CTE is defined by focal deposits of hyperphosphorylated tau in neurons and astroglia at the depths of cerebral sulci and surrounding penetrating blood vessels. The frequency of CTE pathology in the general population, especially former amateur contact sports athletes, is unknown.

Methods: The goal of this study is to identify the known pathognomonic CTE lesions in cortical autopsied tissue from Mayo Clinic Tissue Registry cases (N=2,651) and clinically characterize individuals with and without CTE pathology to establish the relevance of contact sports participation as risk factors of CTE. Using historical obituary and yearbook records, 308 former athletes and 454 non‐athletes were identified. Phospho‐tau immunohistochemistry was performed on three unique neocortical sections (frontal, temporal, and parietal) from these athlete and non‐athlete cases.

Results: Of the 283 cases screened to date, 15 (5.3%) have pathology consistent with CTE. All 15 cases were male and 9/15 had a documented history of contact sports participation (12.2% of known male athletes with CTE).

Conclusion: While additional case screening and clinical characterization remains ongoing, this preliminary data suggests CTE pathology is a common neuropathological finding, especially in individuals with prior documented participation in a contact sport.

Oral 14: O14‐1

Radiological, immunological, and pathological analysis of ependymal cells in neuromyelitis spectrum disorders

Fumihiro Yanagimura¹; Etsuji Saji¹; Takahiro Wakasugi¹; Yasuko Toyoshima²; Akiyoshi Kakita²; Hitoshi Takahashi²; Osamu Onodera¹; Izumi Kawachi¹

¹Department of Neurology, Brain Research Institute, Niigata University; ²Department of Pathology, Brain Research Institute, Niigata University

Objective: Neuromyelitis optica spectrum disorders (NMOSD) is a central nervous system inflammatory autoimmune disease with aquaporin‐4 (AQP4) antibody as a disease‐specific marker. On magnetic resonance images (MRI), although multiple sclerosis (MS) is characterized by a lesion perpendicular to the ventricular wall called Dawson's finger, NMOSD is characterized by a lesion along the ventricular wall called ‘pencil‐thin’ ependymal enhancement. The details of radiological, immunological, and pathological features of the ependymal cells in NMOSD remain elusive. The objective of this study is to clarify characteristic features on the ependymal cells in NMOSD.

Methods: We retrospectively analyzed clinical, immunological and radiological features of 31 cases with NMOSD and 49 cases with MS. We then performed immunohistological examination (AQP4, Iba‐1, activated complement C9neo, CD3, CD20) using other autopsied specimens of NMOSD (15 blocks) and disease control (6 blocks).

Results: On brain MRI, ‘pencil‐thin’ ependymal enhancement was observed in NMOSD (1/31, 3%), but not in MS (0/49, 0%). AQP4 immunoreactivity was extensively disappeared on the ependymal cells (12/15, 80%) in NMOSD, while it was not observed in disease control (0/6, 0%). Furthermore, in the subependymal lesions of NMOSD, activated complement deposition with vasculocentric patterns, granulocytes including neutrophils and eosinophils and activated microglia infiltration were observed.

Conclusion: The ‘pencil‐thin’ ependymal enhancement observed on brain MRI was a unique, but rare finding in NMOSD. The ependymal lesions in NMOSD were considered as ‘AQP4‐pathy’ with complement‐dependent cytotoxicity, similar to white matter lesions with loss of AQP4 immunoreactivity on astrocytes in the spinal cord and optic nerves of NMOSD.

O14‐2

The classification and clinical significances of autoantibodies against astrocytes

Lei Liu¹; Yueshan Piao²; Jiawei Wang^1,3

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Pathology, Xuanwu Hospital, Capital Medical University; ³Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: Astrocytes make up of over 40% of all the cells in the CNS and perform a wide variety of functions. The discoveries of autoantibodies against astrocytic AQP4, GFAP and SOX1 have enriched the contents of neuroimmunology.

Methods: In vitro indirect immunofluorescence assay.

Results: We discriminate antibodies against three types of antigens: 1) membranal antigen, AQP4; 2)cytoplasmic antigen, GFAP; 3) nuclear antigen, SOX1. This characterization has direct implications for diagnostic workup, treatment and outcome. AQP4‐IgG helps to differentiate neuromyelitis optica from multiple sclerosis and form spectrum diseases sharing with it. AQP4‐IgG from patient's serum reacted with rat leptomeninges and vessel wall of brain parenchyma in linear pattern. It also reacted with parenchyma and vessel wall of primate optic nerve in fine linear pattern. GFAP‐IgG is clinically associated with meningoencephalomyelitis. In rat hippocampus, GFAP‐IgG from patient's CSF reacted with the cytoplasm and processes of astrocytes. In primate cerebellum, it reacted with the radial processes of Bergmann glia in the Purkinje cell layer and penetrated the whole molecular layer. SOX1‐IgG is a newly identified paraneoplastic neurological syndrome antibodies. There is intense labeling of the nuclei of rat Bergmann glia with a patient's serum containing SOX1‐IgG. Nuclei of small cell lung cancer cells of the same patient also immunoreacted with commercial SOX1 antibodies.

Conclusion: AQP4‐IgG has been proved to damage astrocytes and caused astrocytopathy. The potential pathophysiological mechanisms of GFAP‐IgG and SOX1‐IgG remain to be explored.

O14‐3

Neuronal surface antibody mediated autoimmune encephalitis and its paraneoplastic linkage

Lei Liu¹; Yueshan Piao²; Jiawei Wang^1,3

¹Department of Neurology, Beijing Tongren Hospital, Capital Medical University; ²Department of Pathology, Xuanwu Hospital, Capital Medical University; ³Medical Research Center, Beijing Tongren Hospital, Capital Medical University

Introduction: Autoimmune encephalitis (AE) belongs to post infectious or noninfectious encephalitis and has ignited great enthusiasm around the world. But not until the discovery of anti‐NMDA receptor antibody did neurologists notice the differences between antibodies against neuronal surface and nuclei.

Methods: Three case reports and review of the literatures. Patients’ sera and CSF were evaluated by indirected immunofluorescence assay on prefixed rat hippocampus and cerebellum. Not only the neuropil staining patterns of different antibodies were compared, but the resected ovarian teratoma, thymoma and small cell lung cancer were analyzed to identify potential auto‐antigens.

Results: According to different immunopathological mechanisms, AE could be roughly divided into forms with cellular and humoral immunity predominant. In terms of tumor associations, AE could be divided into paraneoplastic and non‐paraneoplastic forms. In general, most paraneoplastic AE are cellular immunity predominant with CD8 positive cytotoxic T cells targeting the cell nuclear or cytoplasmic antigens. These T cells infiltrate brain tissue and cause irreversible damages. On the contrary, non‐paraneoplastic AE are humoral immunity predominant with B cells producing antibodies against cell surface antigens. These antibodies, mostly IgG block cell surface amino acid receptors, ionic channels or cell‐adhesion proteins and cause reversible changes by responding to immunotherapies. But there is always an exception to the general rule.

Conclusion: By presenting three cases with occult neoplasm identified and resected, we proved disorders caused by antibodies against neuronal surface antigens, such as NMDA receptor, LGI1, CASPR2 and GABA receptor type B could also be paraneoplastic by nature.

O14‐4

DOCK8 regulates microglial activity in neuroinflammation

Kazuhiko Namekata¹; Xiaoli Guo¹; Atsuko Kimura¹; Nobutaka Arai²; Chikako Harada¹; Takayuki Harada¹

¹Visual Research Project, Tokyo Metropolitan Institute of Medical Science; ²Brain Pathology Research Center, Tokyo Metropolitan Institute of Medical Science

Introduction: Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor. In humans, loss‐of‐function mutations in this gene are responsible for a combined immunodeficiency. In this study, we investigated the role of DOCK8 in microglia using two disease models: experimental autoimmune encephalomyelitis (EAE) for multiple sclerosis (MS), and optic nerve injury (ONI) for glaucoma. Also, we report a novel method for reconstructing 3D images of microglia to examine microglial dynamics.

Methods: A novel mouse line with DOCK8 deletion (DOCK8^‐/‐) was generated. EAE was induced with the myelin oligodendrocyte glycoprotein (MOG)35‐55 peptide. For obtaining 3D images of microglia, the retina, optic nerve or a section of the spinal cord were cleared and immunostained with an iba‐1 antibody.

Results: We show that DOCK8 is expressed in microglia and its expression is increased in the MS patient brain and in mouse EAE. Clinical symptoms of DOCK8^‐/‐ EAE mice were ameliorated and the number of iba‐1 labelled microglia was reduced in the spinal cord and optic nerve of DOCK8^‐/‐ EAE mice. Similarly, ONI‐induced activation of microglia is suppressed in the DOCK8^‐/‐ mouse retina. Furthermore, we demonstrate that DOCK8 deficiency hinders microglial migration and phagocytosis.

Conclusion: DOCK8 is expressed in microglia and DOCK8 deficiency suppresses microglial activity during neuroinflammation. DOCK8 may be a therapeutic target for diseases such as MS and glaucoma. Our novel method for visualizing microglia in 3D images will be a useful tool for studying cellular dynamics.

Symposium 27 (BNS Sponsored): S27‐1

The utility of post mortem radiological imaging in forensic neuropathology practice

Linda E Iles

Forensic Pathology Services, Victorian Institute of Forensic Medicine

Post mortem radiological imaging, most widely available in the form of post mortem CT scanning, if used appropriately, can optimise and value add to the forensic neuropathological examination by assisting in case triage, targeting areas of interest, demonstrating features not readily seen on routine examination, documenting extensive neurosurgical intervention, and providing a complimentary data set, which when added to conventional neuropathological findings, can provide useful case data to forensic investigators. These scenarios will be discussed, along with the utility of post mortem CT angiography.

S27‐2

Vascular complications of traumatic head injury

Daniel du Plessis^1,2

¹Greater Manchester Neurosciences Centre, Salford Royal Hospital; ²Dept of Paediatric Pathology, Alder Hey Children's Hospital

Secondary vascular compromise is a common complication of post‐traumatic brain swelling, comprising global hypoxic‐ischaemic brain injury, bleeds and herniation‐related infarction. Primary cranio‐cervical arterial and/or venous injuries are less commonly encountered. Such pathologies are though under‐recognised, a status contributed to by limited reporting in the literature, compounded by poor documentation and suboptimal investigative approaches in the past. Despite the relatively rare occurrence of such pathologies, a pro‐active, anticipatory approach to such injuries should be promoted in forensic practice. It is further necessary to emphasize that some such vascular injuries may only require minor trauma and on occasion occur spontaneously, mimicking traumatic head injury including non‐accidental injury. A high index of suspicion is essential to avoid diagnostic neglect or error. Traumatic basal subarachnoid haemorrhage serves as a model in this regard, the diagnosis and recognition of which has benefited from more rigorous, focused dissection and sampling protocols. Pathophysiological issues around cause and effect though remain to be elucidated fully. The spectrum of traumatic arterial vascular traumatic injury further includes cranio‐cervical arterial dissection and traumatic intracranial aneurysms. Some such injuries have been described in a setting of relatively minor trauma, again focusing attention on susceptibility factors including underlying, predisposing connective tissue disorders. Cerebral venous thrombosis is another under‐recognised complication of traumatic head injury in all age groups. CVT attracted some controversy following a suggestion that complications may mimic paediatric non‐accidental head injury.

S27‐3

Inflicted traumatic brain injury in infants: An update on neuropathology and ophthalmopathology with a reassessment of the role of the brainstem

Jakob Matschke^1,2

¹Forensic Neuropathology Unit; ²Institute of Neuropathology University Medical Centre Hamburg‐Eppendorf

Inflicted traumatic brain injury in infants comprises mostly the so‐called shaken baby syndrome and a few other rarer conditions. Neuropathologists are often asked to give oral or written expertise for investigative authorities. Yet an expertise in a manner that will stand up in court requires a broad knowledge of the pathomorphology and a sound understanding of the underlying pathomechanisms. This talk will summarize the current knowledge of inflicted traumatic brain injury in infants and give an critical overview of its facts, myths and controversies. A special consideration is given to the role of local traumatic injury to the brainstem and the pathophysiological consequences hereof.

S27‐4

Brain Swelling: Issues of Recognition, Aetiology and Timing – Insights from the Hillsborough Stadium disaster in the United Kingdom

Daniel du Plessis

Greater Manchester Neurosciences Centre and Alder Hey Children's Hospital, Liverpool

The 1989 Hillsborough Stadium disaster was the worst British sporting disaster. The original inquests controversially determined that all deaths occurred shortly after a sudden influx of spectators. A 2012 review concluded that several of the 96 fatalities might have survived, an opinion in part informed by the original post‐mortem examination findings, which suggested that many victims had brain swelling and were thus subject to more prolonged survival. Review of the postmortem findings to assist the 2014 reinquests expressed concern about the accuracy of such descriptions, although brain weights were disproportionately high. It was also concerned by the incorrect assumption that brain swelling necessarily reflected cerebral oedema. Consideration was given to alternative (and far more rapid) mechanisms of brain swelling such as perfusion swelling due to loss of autoregulation or passive congestion due to venous outflow obstruction. Comparison with other modes of asphyxial death including hangings or static forms of crush asphyxia provided some possible further insight. Crush asphyxia in a crowd situation may be subject to more complex pathophysiology given a waxing and waning effect rather than static compression.

Review of the neuropathology of the 96 deaths highlighted pitfalls in the assessment of brain swelling at postmortem and emphasized the need for an integrated approach relying on a combination of features to enhance objectivity and reliability. It also emphasizes the necessity not to assume that all swelling is oedema as the latter may have profound medico‐legal implications in terms of potential survival.

S27‐5

SUDEP as a cause of sudden death

Maria Thom

Department of Neuropathology, Institute of Neurology University College London

Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults with epilepsy. The incidence is estimated as 1 to 2 cases per 1000 people with epilepsy per year from population based studies. SUDEP is geographically widespread, can affect all age groups and epilepsies with diverse underlying causes with frequent generalised seizures being the greatest risk factor. The years of potential life lost from SUDEP is second only to stroke for neurological conditions and the International League Against Epilepsy (ILAE) now recognises SUDEP as a global healthcare concern which has been previously underestimated. SUDEP is defined as an unexpected and non‐accidental death in patient with epilepsy (excluding status epilepticus), where no cause of death is identified following complete post‐mortem examination. Deaths occur around the time of a seizure, although many are unwitnessed. Although the mechanisms and pathophysiology are still uncertain, accumulating evidence from clinical, imaging (structural and functional imaging) and experimental studies indicates that central autonomic regulatory control of vital cardio‐respiratory functions is involved.

It is vital that a uniform and standardized autopsy and neuropathological examinations are conducted in these cases for correct cause of death categorization of SUDEP and its distinction from other epilepsy related deaths. Furthermore, systematic post mortem tissue banking in conjunction with parallel molecular genetic analysis will be vital to further future research programs. For example, recent neuropathology studies have highlighted alterations to neuromodulatory neuronal networks in the medullary respiratory nuclei and central autonomic networks including the amygdala in SUDEP. One hypothesis therefore is that epilepsy and seizures induce aberrant modulation and plasticity in brainstem and central autonomic networks that render the brain more likely to dysfunction during seizure.

This talk aims to overview the current understanding of the neuropathology findings in SUDEP and how tissue based studies could advance our understanding of disease mechanisms.

Symposium 28: S28‐1

Neuropathology of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) presenting as either PSP syndrome (PSPS) or corticobasal syndrome (CBS)

Dennis William Dickson; Shunsuke Koga

Department of Neuroscience, Mayo Clinic

Introduction: PSP and CBD are 4R‐tauopathies with overlapping clinical and pathologic features that lead to diagnostic difficulties.

Methods: The Mayo Clinic brain bank has 1271 patients with PSPS and 236 with CBS. We reviewed neuropathology to provide insights on diagnostic accuracy.

Results: Of patients with PSPS, 1031 had PSP (81% diagnostic accuracy). Other disorders were CBD (6%), Lewy body disease (LBD, 4%), multiple system atrophy (3%), Alzheimer disease (AD, 2%) and cerebrovascular disease (vascular PSP, 1%). For patients with CBS, 61 had CBD (26%). Other disorders were PSP (33%), AD (21%), LBD (6%), frontotemporal lobar degeneration (5%), primary lateral sclerosis (3%) and Pick disease (2%). PSPS with PSP were older at death than those with CBD (74 vs. 69 years). PSPS with PSP had more Alzheimer pathology that PSPS with CBD (median Braak: III vs. I; median Thal: 1 vs. 0). There were no demographic differences in patients with CBS and either PSP or CBD. Almost half of PSP with CBS were atypical PSP, with corticospinal tract degeneration in 48%. In contrast, 5% of CBD with PSPS had atypical pathology and greater hindbrain tau pathology. Argyrophilic grain disease was more frequent in CBD (49%) than PSP (24%), but it had no clear relationship to clinical presentation. TDP‐43 pathology was greater in CBD (47%) than PSP (4%). In CBD it was associated with PSPS (60% vs. 30%).

Conclusions: Specific pathologic features distinguish PSPS with underlying PSP versus CBD that may lead to biomarkers to improve diagnostic accuracy.

S28‐2

Neuropathology of Parkinson's disease as multicentric Lewy body disorder

Koichi Wakabayashi

Department of Neuropathology, Hirosaki University

The histological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is neuronal alpha‐synuclein aggregates called Lewy bodies and Lewy neurites. To date, more than 100 molecules have been identified in Lewy bodies, in which phosphorylated alpha‐synuclein is a major constituent. PD is traditionally considered a movement disorder with lesions in the brainstem pigmented nuclei. However, accumulating evidence suggests that non‐motor complications are also common in PD. Braak et al. proposed a pathological staging scheme for PD, in which early alpha‐synuclein pathology is present in the dorsal vagal nucleus and in the olfactory bulb. This staging system characterizes a progression from the dorsal vagal nucleus (stage 1), through the pontine tegmentum (stage 2), into the midbrain and neostriatum (stage 3), and then the basal procencephalon and mesocortex (stage 4), and finally through the neocortex (stages 5 and 6). Braak PD stages 1‐3 correspond to incidental Lewy body disease (ILBD), which is considered to represent the presymptomatic PD and/or DLB. In PD and DLB, Lewy bodies and Lewy neurites are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. In ILBD, Lewy bodies occur in the brain, spinal cord, sympathetic ganglia, visceral autonomic nervous system and skin. In addition, neuronal loss is found in the substantia nigra, striatum and heart in ILBD. The pathological process of Lewy body disease may target the peripheral and central nervous systems at the same time.

S28‐3

Evolving concepts of globular glial tauopathies

Gabor G. Kovacs

Institute of Neurology, Medical University of Vienna, Vienna, Austria

Recent studies have highlighted a group of 4‐repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular, usually Gallyas negative astroglial, and Gallyas positive oligodendroglial inclusions. The overarching term globular glial tauopathy (GGT) has been recommended for three different morphological subtypes distinguished based on the anatomical and cellular (astroglial or oligondendroglial) predominance of pathology. The clinical presentation ranges from behavioral variant of FTD, progressive aphasia, corticobasal syndrome to features of motor neuron disease or other movement disorders. By electron microscopy, oligodendroglial inclusions show granular material and haphazardly oriented filaments. Interestingly occasionally oligodendroglial but not astroglial inclusions can be 3R positive. Neurons show diffuse cytoplasmic immunoreactivity or globular or tangle‐like tau immunoreactivity, which also contain the 4R‐tau isoform. GGT has been seen also in elderly individuals. Concomitant proteinopathy is not a consistent feature, however, there are cases, which show neuronal and glial TDP‐43 lesions in the same affected areas or only in the limbic system as seen for example in Alzheimer disease. Similarity of the oligodendroglial tau pathology to that seen in the α‐synucleinopathy multiple system atrophy (MSA) with a different anatomical vulnerability pattern has been noticed. Studies on oligodendroglial response in GGT and MSA show similarities such as loss of nuclear TPPP/p25α immunoreactivity correlating with tract degeneration and enlarged cytoplasmic TPPP/p25α immunoreactivity. However, distinct features, such as more colocalization of α‐synuclein than tau with TPPP/p25α can be also recognized. In summary, GGTs represent a peculiar subgroup of neurodegenerative diseases emphasizing the role of the neuroglia in the pathogenesis of these conditions.

S28‐4

Multiple system atrophy: glial and neuronal synucleinopathy

Mari Yoshida

Institute for Medical Science of Aging, Aichi Medical University

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by various combinations of autonomic failure, levodopa‐unresponsive parkinsonism, cerebellar ataxia, or pyramidal signs. The histopathological hallmark is the oligodendrocytic glial cytoplasmic inclusions (GCIs) consisting of abnormal alpha ‐synuclein aggregation (AS). MSA was previously considered three distinct diseases: striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) and Shy‐Drager syndrome. Depending upon the predominant motor symptom, the current consensus criteria for diagnosis of MSA defined two clinical phenotypes: MSA with predominant cerebellar ataxia (MSA‐C) and MSA with predominant parkinsonism (MSA‐P). Previous studies have reported some cases of MSA patients presenting with severe autonomic failures in the absence of the diagnostic motor signs of MSA, which were referred to as non‐motor MSA. These reports have revealed the mild pathological feature of OPCA and SND with the presence of GCIs in vulnerable regions. AS is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. A subgroup of MSA cases with temporofrontal atrophy showed numerous NCIs, particularly in the limbic system. These findings suggest the expanding range of neuronal pathology in MSA. For better understanding of pathological spectrum in MSA, we review the pathological features of the literature and nearly 180 MSA cases in the Brain Resource Center of Institute for Medical Science of Aging, Aichi Medical University.

Symposium 29: S29‐1

Pilocytic astrocytoma with anaplastic features

Fausto Rodriguez

Division or Neuropathology, Johns Hopkins University School of Medicine

Pilocytic astrocytomas (PA) are well differentiated astrocytic neoplasms representing the most frequent primary brain tumors in children. Numerous studies have demonstrated that a tandem duplication involving the kinase domain of BRAF and leading to a novel fusion (KIAA1549‐BRAF) is present in most sporadic PA. PA is assigned a WHO grade I designation given its slow growth potential, long patient survival and potential for cure when totally resected. However, a small subset of PA develop anaplastic changes either de novo or in the setting of prior irradiation. We previously developed diagnostic criteria for these tumors, which included brisk mitotic activity with or without necrosis. These findings were associated with a worse prognosis, akin to diffuse gliomas when compared to historic cohorts. We have also documented frequent PI3K/mTOR activation, in addition to MAPK activation, and deletions involving PTEN and CDKN2A. A recent study by Reinhardt et al. reported a separate molecular methylation class corresponding to a subset reported as anaplastic astrocytoma with piloid features, which is characterized by frequent CDKN2A and ATRX alterations. In the recent update of our experience, we studied 57 resections from 36 patients (23 M, 13 F, mean age 32 years, range 3‐75 years). ALT and ATRX loss, as well as alterations involving the MAPK pathway, were frequent. Additionally, a small subset demonstrated H3‐K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with potential for aggressive clinical course, heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

S29‐2

Atypical teratoid/rhabdoid tumors arising from gliomas: Histopathological and genetic features of four cases

Junko Hirato¹; Sumihito Nobusawa²

¹Department of Pathology, Gunma University Hospital; ²Department of Human Pathology, Gunma University Graduate School of Medicine

Atypical teratoid/rhabdoid tumor(AT/RT) is a malignant CNS tumor showing rhabdoid cells, polyphenotypic differentiation, and inactivation of SMACB1/INI1 or SMARCA4/BRG1. Most AT/RTs occur de novo; however, they can rarely arise in other tumors. Here, we investigated the histopathological and genetic features of four cases of these tumors, consisting of INI1‐deficient rhabdoid cell components and gliomas, to clarify the characteristics of secondary AT/RTs. They included a 27‐year‐old woman with a para‐hippocampal tumor (case 1), a 22‐year‐old woman with an occipital lobe tumor (case 2), one‐year and 11‐month‐old female infant with a frontal lobe tumor (case 3), and a 24‐year‐old man with a frontal lobe tumor (case 4). Glioma components of these tumors were pleomorphic xanthoastrocytoma(PXA), anaplastic PXA, low‐grade astrocytoma, and ependymoma, respectively. INI1‐deficient rhabdoid components of the cases with PXA and anaplastic PXA showed plump eosinophilic cytoplasm, irregular‐sized nuclei, and pleomorphism including sickle‐shaped nuclei mimicking epithelioid glioblastoma. In case 3, an INI1‐deficient component was composed of not only rhabdoid cells, but also epithelioid, pale, and vacuolated cells, resembling de novo AT/RTs. In the results of genetic analysis, FISH analysis detected LOH of 22q in the rhabdoid component of case 1 and both rhabdoid and lower‐grade components in the tumors of cases 2 and 4. Direct sequencing for the INI1 mutation identified only the AT/RT component of case 3. Histological features of secondary AT/RTs may be different from de novo AT/RT depending on paternal tumors. There is a possibility that the genetic status of INI1 also affects morphological features.

S29‐3

Diffuse midline gliomas H3 K27M‐mutant: An update

Chitra Sarkar; Kavneet Kaur; Anupam Kumar; Pankaj Pathak; Vaishali Suri; Mehar Chand Sharma; Ajay Garg; Ashish Suri

Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi

Diffuse midline gliomas (DMG), recognized as a new diagnostic entity in the updated 2016 WHO classification, are infiltrative midline high grade gliomas, which harbour K27M mutation in histone genes, H3F3A or HIST1H3B/C. They occur predominantly in children (median age 5 11 years), but can also be seen in adults. These tumors involve midline structures, the most common locations being brainstem, thalamus and spinal cord. They exhibit a wide morphological spectrum with features overlapping nearly all histological variants of astrocytic tumors. These are aggressive grade IV tumors with 2 year survival rate of around 10%. The use of H3K27M mutant specific immunohistochemistry is useful to identify the mutation and therefore very helpful for the diagnosis of this entity. In our own series of 46 midline astrocytic tumors, 60% were H3 K27M mutant. Distinct differences were noted between adult and pediatric midline gliomas as well as H3 K27M mutant and wild type midline gliomas. Clinical outcome of the mutant cases was significantly worse. Interestingly, the same mutation has recently been observed in many other tumors such as ependymomas and pilocytic astrocytomas, with no distinct prognostic significance. For these reasons, the Working Committee 3 (cIMPACT NOW update 2) have provided diagnostic clarifications for this entity viz. that the term diffuse midline glioma, H3 K27M mutant should be reserved for tumors that are diffuse (i.e. infiltrating), midline (thalamus, brainstem, spinal cord etc.), gliomas and H3K27M mutant, and should not be applied to other tumors that are H3 K27M mutant.

S29‐4

Anaplastic Pleomorphic Xanthoastrocytoma

Maysa A. Al‐Hussaini

Department of Pathology and Laboratory Medicine, King Hussein Cancer Foundation, King Hussein Cancer Center

Pleomorphic xanthoastrocytoma (PXA) is a well categorized brain tumor that affects children and young adults. It primarily presents with seizure and a cystic lesion with mural nodule centered in the cortex, most commonly in the temporal lobe, is the classical radiological finding. It is associated with prolonged survival if completely excised and is assigned a grade II by the WHO. Anaplastic PXA (aPXA) has recently been officially recognized as a grade III tumor and appears as a distinct entity in the 2016 WHO Classification of Tumours of the CNS. To be eligible for aPXA, the tumor should have an excess of mitotic figures (= and > 5mitoses/10HPFs). The presence of the necrosis is an additionally, but none core criteria. aPXA is associated with dismal outcome. The recent association of PXA with BRAF V600E mutation has opened the door for a better control of the tumors with potential response to targeted therapies. Testing for BRAF V600E mutation has become a cornerstone in the management of PXA and aPXA cases. The differential diagnosis for aPXA includes other high grade gliomas, especially glioblastoma (GBM). The relation of aPXA with GBM, in particular epithelioid GBM, especially in view of the BRAF V600E mutation in the latter will be discussed.

Poster Session 3: P3‐1

Photobiomodulation following Traumatic Brain Injury

Amir Oron¹; Uri Oron²

¹Department of Orthopedics, Kaplan Medical Center; ²Department of Zoology, Tel Aviv University, Israel

Photobiomodulation has been found to modulate various biological processes including traumatic brain injury (TBI). Following TBI in mice, in this study we assessed the use of several photobiomodulation protocols producing a beneficial effect on the long‐term neurobehavioral outcome and brain lesions of these mice. TBI was induced by a weight‐drop device, and neurobehavioral function was assessed from one hour and up to 56 days post‐trauma using a neurological severity score (NSS). The extent of recovery is expressed as dNSS, the difference between the initial score, and that at any other, later, time point. An 808nm Ga‐Al‐As diode laser was employed transcranially 4, 6 or 8 hrs post trauma. Mice were divided into several groups. MRI was done prior to sacrifice. From 5 to 28 days post‐TBI, the NSS of the laser‐treated mice were significantly lower (p<0.05) than the control mice. The percentage of surviving mice that demonstrated full recovery 56 days post‐CHI, namely NSS=0 (as in intact mice) was the highest (63%) in the group that had received photobiomodulation at 100 Hz. In addition, MRI analysis demonstrated significantly smaller infarct lesion volumes in laser treated mice as compared to control. Our data suggest that non‐invasive photbiomodulation of mice post‐TBI provides a significant long‐term functional neurological benefit, and that 100 Hz is optimal for such treatment.

P3‐2

Oligodendroglioma, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation of a 31‐year‐old male: A case report and literature review

Yangki Minn¹; Seonghye Choi²; Se Hoon Kim³; Yoon Jin Cha⁴

¹Department of Neurology, Hallym Univeristy College of Medicine, Kangnam Sacred Heart Hospital, Seoul, Korea; ²Department of Neurology, Inha University College of Medicine, Inha Hospital, Incheon, Korea; ³Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea; ⁴Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea

Introduction: Oligodendroglioma (OLG) is a diffusely infiltrating glial neoplasm. Sporadic case reports of neuronal differentiation of OLG and subset of neuronal gene expression of OLGs have been identified. Here, we report a rare case of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation in a 31‐year‐old male patient.

Clinical summary: A 31‐year‐old male patient without specific medical history was admitted with a seizure. Brain computed tomography revealed 7cm‐sized contrast enhancing cystic mass with internal necrosis and calcification, in the right frontal lobe. With suspicion of anaplastic OLG, gross total removal of the tumor was performed. Patient is alive well after subsequent radiotherapy.

Pathologic findings: On microscopic examination, diffusely infiltrating tumor cells with clear cytoplasm were found in the cortex. Necrosis or endovascular proliferation was not found. Majority of tumor was composed of OLG‐like clear tumor cells with chicken‐wire pattern vasculatures. Throughout the tumor, atypical gangliocyte‐like cells having hyperchromatic nulcei, prominent nucleoli and ample cytoplasm were observed. Differential diagnoses included ganglioneuronal tumors and OLG with gangliocytic differentiation. Tumor cells were diffusely positive for OLIG2 and IDH (R132H) immunohistochemical stainings (IHC). Scattered ganglion‐like cells were highlighted by NeuN and synaptophysin IHC. Subsequent fluorescence in situ hybridization analysis revealed 1p/19q codeletion, confirmed the diagnosis of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation.

Conclusion: Although rarely found, OLG can have neuronal differentiation and may present like long‐term epilepsy associated tumor and lead to underdiagnosis. IDH analysis, preferentially IDH1 IHC would help to discriminate OLG from other glioneuronal tumors.

P3‐3

Histomorphological patterns of glioblastoma and its rare variant: a case series in the Indian subcontinent

Madhu Kumar; Suresh Babu; Madhu Mati Goel; B K Ojha

King George's Medical University

The adult population, and about 75% of all the anaplastic gliomas. The prevalence of GBM is about 2‐4 cases per 100,000. It is more common in men than in women, and its incidence increases with age. Variants of glioblastoma, poses both diagnostic and therapeutic challenges.

Clinical summary: A reterospective case series included 11 cases of glioblastoma with its variant at the tertiary care centre. All of the patients presented with on and off headache, seizures, vomiting, and focal neurological deficit. The mean age was 44.6years. Radiological examination revealed as supratentorial mass, most common sites included temporal, frontal, followed by temporo‐perital and occipital. Surgical craniotomy was done and tumor specimen was sent for histopathological diagnosis.

Pathological findings: On histological analysis, sections shows infiltrating growth pattern, arranged in nests and sheets, with marked nuclear atypia, giant cell astrocytes, multinucleated tumor cells, epitheloid like cell, spindle cells, bizarre nuclei, areas of necrosis, microvascular proliferation and haemorrhage are also evident. Provisional diagnosis was glioblastoma. GFAP, CD99, CD56, Vimentin, myogenin, Synaptophysin, LCA, EMA, Ki67 immunohistochemical stains were done. Out of 11 cases, 2 cases of epitheloid GBM, 4cases of giant cell GBM, 3 cases of gliosarcoma, and 2 case of primitive neuronal component were reported after immunochemistry, which help us to arrive at the final diagnosis.

Conclusion: Glioblastoma is the most common primary brain tumor in adults. The immunohistochemical stains make the diagnosis of GBM with its variants much easier and rule‐out other differential diagnoses.

P3‐4

Clinicopathologic features of an autopsied patient with epithelioid glioblastoma: experience of BRAF and MEK inhibitor treatment

Yu K^1,2; Rie S¹; Manabu N²; Makoto O²; Yukihiko F²; Akiyoshi K¹

¹Departments of Pathology, Brain Research Institute, Niigata University; ²Departments of Neurosurgery, Brain Research Institute, Niigata University

Introduction: Epithelioid glioblastoma (E‐GBM) is a rare aggressive glioblastoma (GBM) variant. Approximately 50% of E‐GBM harbors the BRAFV600E mutation. However, it has been unclear whether the BRAF and other molecular profiles might influence on clinicopathologic features of the patients. Recently, we experienced a patient with E‐GBM, for whom we tried BRAF and MEK‐targeted therapy. Here, we described clinical and autopsied features of this patient.

Clinical and pathological summary: The patient, a 57‐year‐old Japanese man, was admitted to a hospital because of headaches. A brain MRI study demonstrated a well‐circumscribed mass in the left frontal lobe with gadolinium enhancement. Subtotal removal of the tumor was performed. Histopathologically, the tumor was composed of monotonous, discohesive patternless sheets of medium‐sized rounded cells with abundant eosinophilic cytoplasm. Immunohistochemically, the cells were positive for S‐100 protein and INI‐1, but negative for IDH‐1, GFAP or cytokeratin. A pathological diagnosis of E‐GBM was made. A gene sequencing analysis revealed BRAFV600E, TERT (C250T) promotor mutation, and CDKN2A/2B loss. Postoperative radiotherapy and concomitant temozolomide therapy were performed, but the tumor disseminated into the subarachnoid space. BRAF and MEK‐targeted therapy was introduced, but the effects appeared temporarily. The patient died 8 months after onset. At autopsy, massive leptomeningeal dissemination composed of E‐GBM cells was evident. Surprisingly, tumor cells invading the brain parenchyma were rarely seen.

Conclusion: The clinicopathologic features and genetic profiles of this patient are distinct from those of GBM. Further analyses are needed for better understanding the pathomechanisms underlying this malignant brain tumor.

P3‐5

Features of IDH‐ and H3F3A‐mutated cerebellar high‐grade gliomas of Japanese cases.

Nozomi Matsumura¹; Satoshi Nakata^1,2; Tatsuya Yamazaki¹; Sumihito Nobusawa¹; Hayato Ikota¹; Junko Hirato³; Hideaki Yokoo¹

¹Department of Human Pathology, Gunma University Graduate School of Medicine; ²Departments of Neurosurgery, Gunma University Graduate School of Medicine; ³Departments of Diagnostic Pathology, Gunma University Hospital

Introduction: Isocitrate dehydrogenase (IDH) ‐mutated or H3 K27M‐mutated adult cerebellar high‐grade gliomas (HGG) are rare. We analyzed two IDH‐ and two H3F3A‐mutated adult cerebellar HGG cases histologically and genetically.

Methods: For histological analyses, some primary antibodies including glial or neuronal markers were selected. The mutation statuses were assessed by direct sequencing.

Results: The HGG case with IDH1 R132H mutation was an 83‐year‐old man, whose tumor was mainly composed of densely packed round‐to‐polygonal tumor cells resembling epithelioid cells. High mitotic activity was observed, and vascular wall invasion was often detected. INI1 expression was retained in nuclei. The IDH2 R172K‐mutated 75‐year‐old woman's case was high‐grade astrocytoma with an area of tumor cells forming a cord‐like architecture or perivascular arrangement surrounded by a myxoid matrix. In both IDH‐mutated cases, palisading necrosis and microvascular proliferation were absent, and ATRX expression was retained. One of H3F3A K27M‐mutated HGG was occurred in 70‐year‐old woman, accompanied by a limited low‐grade area showing the aggregation of plump tumor cells with an eosinophilic granular cytoplasm. Another H3F3A K27M‐mutated case was a 68‐year‐old man, whose tumor was composed of diffusely proliferating atypical cells with high mitotic activity and hemorrhagic necrosis. DNA sequencing revealed that HIST1H3B, BRAF, and TERT promoter were wild type in all four cases. Literature reviews uncovered that infratentorial IDH‐mutated gliomas are prone to show mutations other than IDH1 R132H, and cerebellar H3 K27M‐mutated cases were all adults.

Conclusion: We presented rare adult cerebellar HGG with IDH‐ or H3F3A‐mutations, and showed several clinicopathological features.

P3‐6

YAP/TAZ expression correlated with angiogenesis in astrocytoma

Chenyue Xu¹; Luning Mao¹; Ji Xiong²; Yin Wang²; Ying Liu¹

¹Department of pathology, Basic Medical Science, Fudan Uiversity; ²Department of Pathology, Huashan Hospital, Fudan University

Recent studies reports YAP/TAZ act as a major regulator of physiological embryo angiogenesis. YAP/TAZ transmits the VEGF/VEGFR2 signaling into a specific transcriptional program, essential for vascular tip cell migration, blood vessel formation, and vascular barrier maturation in the sprouting angiogenesis of retina and brain during embryonic development. Glioblastoma multiform (GBM) is one of the most vascularized of all the human tumors. The presence of microvascular proliferation is a histopathological hallmark of glioblastoma. Therefore, the role of YAP/TAZ in pathological angiogenesis, especially in GBM blood vessel proliferation need to be verified. The large human astroglioma samples were used for detecting the expression of YAP/TAZ. The correlation between the vascular density and clinical blood perfusion in GBM were detected. In astrocytoma, the expressions of YAP/TAZ in both endothelial cells and tumor cells were increased with the malignant grade. In endothelial cells, the YAP/TAZ expression was positively correlated with the blood vessels density. In GBM, the YAP/TAZ positive staining was stronger in the glomerular type than that in the thin‐walled type neovascularization. The YAP/TAZ expression also positively correlated with the VEGFR expression on the endothelial cells. Our studies indicated the critical role of VEGFR/TAZ signaling pathway involved in the endothelial proliferation in astrocytoma.

P3‐7

mTORC2 regulates hypomethylator phenotype in glioblastoma

Mio Harachi; Erika Shimizu; Kenta Masui; Noriyuki Shibata

Department of Pathology, Tokyo Women's Medical University

Introduction: Recent studies have demonstrated that glioblastoma (GBM) shows a decrease in DNA methylation on recurrence or malignant progression. From a therapeutic point of view, it is important to unravel how DNA hypomethylator phenotype is regulated in GBM. Here, we set out to determine the role of epidermal growth factor receptor (EGFR)‐mammalian target of rapamycin (mTOR) pathway, which is hyper‐activated in most GBM cases, in DNA hypomethylator phenotype.

Methods: To uncover the regulatory mechanism of DNA hypomethylation and its functional consequences, we interrogated cell lines and clinical samples of GBM, the highly lethal brain cancer in human.

Results: We discovered that in GBM, mTORC2, one of the mTOR complexes, induced DNA hypomethylation by suppressing the expression of DNA methyltransferase 3A (DNMT3A). Activation of mTORC2 enhanced TERT (telomerase reverse transcriptase) mRNA expression through demethylation of its promoter. Of note, GBM cells were addicted to overexpressed TERT for their survival.

Conclusion: In GBM, mTORC2 regulates DNA hypomethylator phenotype and facilitates tumor cell survival through promoting the expression of specific oncogenes.

P3‐8

Glioblastoma, subependymoma and meningioangiomatosis; collision of three morphologically and genetically different entities in one patient

Elizabeth Jean Cochran¹; Jennifer Connelly²; Alexander Mackinnon¹

¹Department of Pathology, Medical College of Wisconsin; ²Department of Neurology, Medical College of Wisconsin

Introduction: Occurrence of multiple different primary brain tumors in one patient is rare. We report a patient with a subependymoma, meningioangiomatosis, and glioblastoma.

Clinical summary: The patient was 61‐year old man who presented with headaches; brain MRI showed a left intraventricular mass. Pathology demonstrated a subependymoma, WHO grade I. Four years later, routine MRI showed an enhancing right frontal lesion; pathology was meningioangiomatosis. Eighteen months later, he presented with new‐onset seizures. Brain MRI showed a left frontal enhancing mass; pathology was glioblastoma, IDH‐wildtype. One month later, he died, and underwent brain autopsy.

Pathological findings: Surgical and autopsy tissue was examined, and molecular analysis with next generation sequencing was performed on each primary brain lesion using the Ion AmpliSeq Cancer Hotspot Panel v2, which targets clinically important regions of 50 cancer‐related genes. Molecular analysis of each brain lesion showed the following results: glioblastoma‐PTEN L295fs (C. 882delT). Notch1 V1578del was identified in meningioangiomatosis with very low allelic frequency (1%), pending confirmation. The subependymoma had no mutations. No variants in other genes on the panel were identified.

Conclusion: PTEN mutation, present in this glioblastoma, and not mutated in the subependymoma or meningioangiomatosis, is reported to be mutated in 30% of glioblastomas. NOTCH1 gene mutation, detected in the meningioangiomatosis lesion, has not been reported in this entity, and was not present in the two tumors. Further studies to verify this finding are ongoing. These results support that these lesions are likely collision tumors/processes, occurring in a single individual without a known cancer predisposition syndrome.

P3‐9

Gliosarcoma with arterial invasion. Report of two cases

Erick Gomez‐Apo; Sebastian Coronel‐Montero; Gerardo Aristi‐Urista; Luis Manola‐Aguilar; Eric Mendoza‐Oviedo; Carlos Mendoza‐Garcia; Laura Chavez‐Macias

General Hospital Of Mexico

Background: Ischemic strokes in patients with primary brain tumors are a postoperative complication or a complication of radiation therapy. Rarely, direct vessel occlusion by an adjacent primary brain tumor may cause a large vessel ischemic stroke.

Clinical Cases: Case 1. A 68‐year‐old man. He started three months before his death with headache, dysarthria and hemiparesis. RMN reported a frontal tumor of 4.8 cm. He continued with drowsiness, left hemiparesis, cough and tachypnea. Surgery was not‐accepted, and he died. Case 2. A 68‐year‐old man. He started fifteen months ago, with headache, disorientation and stupor. RMN reported tumor in right hemisphere brain with measures of 12x10x7 mm. Tumor was 90% resected and he received adjuvant radiotherapy. One year later, he was diagnosed with residual/recurrent tumor; he was treated with anti‐edema management and he died at home.

Histopathological Findings: Case 1. On autopsy, we observed a tumor of 5.5 cm on left hemisphere. At the periphery, there was a triangle injury with liquefy aspect. On microscopy, injury was due to gliosarcoma and ischemic changes in peripherical tissue; the lumen of middle cerebral artery was necrosis and few neoplastic cells. Case 2. On biopsy, there was a gliosarcoma, one artery had evidence of invasion into tunicas and lumen.

Conclusions: Tumor‐related ischemic strokes are most unusual in patients with malignant gliomas. This event is uncommon for gliosarcomas; authors have knowledge of an only report of a 46‐year‐old person with microscopic confirmation of invasion of tumour cells into the wall of a greater pre‐existing blood vessel.

P3‐10

Temozolomide and Notch inhibitor MRK‐003 induce cell protective autophagy in malignant gliomas

Manabu Natsumeda^1,2,3; Hiroshi Aoki¹; Hiroaki Miyahara^2,3,4; Akiyoshi Kakita²; Hitoshi Takahashi²; Charles G. Eberhart³; Yukihiko Fujii¹

¹Department of Neurosurgery, Brain Research Institute, Niigata University; ²Department of Pathology, Brain Research Institute, Niigata University; ³Department of Pathology, Johns Hopkins University School of Medicine; ⁴Department of Pediatrics, Oita University School of Medicine

Background: Autophagy is a process in which intracellular proteins are sequestered, delivered to lysosomes and digested. Controversy remains whether autophagy induced by treatments in cancer are cell killing or protective. We set out to determine what type of autophagy is induced by temozolomide and Notch inhibitor MRK003 in gliomas.

Methods: Two glioblastoma neurosphere lines (JHH520 and HSR‐GBM1) were treated with DMSO, 0.5‐5 µM of MRK003, and/or 10 µM choloroquine. Western blotting was performed to detect alterations in LC3B, p62 and cleaved PARP. Cell viability, proliferation, apoptosis, cell cycle and clonogenicity assays were performed to look at the combinatorial effects of MRK003 and the late stage autophagy inhibitor chloroquine. Similar experiments were performed to look at effects of temozolomide. Furthermore, 14 glioma patients who underwent surgical removal before and after treatment with temozolomide were stained for autophagy markers LC3B, LAMP1 and LAMP2A.

Results: An LC3B‐II band, suggesting induction of autophagy, was observed after Notch pathway blockade and temozolomide treatment. Decreased growth (p < 0.001), proliferation (p < 0.05), increased apoptosis (increased sub‐G1 p < 0.05; increased Annexin V percentage: p < 0.05, increased cleaved PARP expression), and decreased clonogenicity were seen after combination MRK003 and CQ treatment compared to DMSO. Staining for autophagy markers was significantly increased in surgically obtained tissues after temozolomide treatment.

Conclusion: Induction of cell protective autophagy occurs after Notch inhibition and temozolomide treatment in glioma cell lines. Inhibition of autophagy is a possible new treatment strategy to overcome resistance to such treatments in gliomas.

P3‐11

T‐LAK cell‐originating protein kinase (TOPK) in adult malignant glioma: Clinico‐pathological and Immunohistochemical Study

Changshu Ke¹; Meng Yan^1,2; Lin Liu³; San‐peng Xu¹; Jing Xiong¹; Sheng Zhou¹; Bei Liu²; Huaqiu Zhang⁴; Ting Lei⁴; Qiu‐hong Duan³

¹Departments of Pathology, Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology; ²Department of Pathology, Affiliated Tianyou Hospital of Wuhan University of Science and Technology; ³Dept. of Biochemistry and molecular biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology; ⁴Dept. of Neurosurgery, Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology

Introduction: In order to investigate pathogenesis of T‐lymphokine‐activated killer cell‐originating protein kinase (TOPK) in adult malignant glioma.

Methods: The TOPK protein expression in glioma was examined by Western blot. Immunohistochemistry was performed to detect the TOPK, EGFR, TP53, c‐myc, and Ki67 labeling index (LI) in 75 cases of adult malignant gliomas (grade II: III: IV = 1:1.05:1.7), the IDH1 status was determined immunohistochemically in 62 cases with IDH1‐positive rate 33.9%. Semi‐quantified expression levels were analyzed between low grade glioma (LGG, grade II) and high grade glioma (HGG, grade III/IV) groups.

Results: The expression of TOPK protein in glioma was demonstrated by Western blot and immunohistochemistry. Strong nuclear staining of TOPK in HGG and moderate/focal nuclear staining in LGG were appreciated. The expression of TOPK and Ki67 LI were both significantly higher (P<0.01) in HGG than LGG. Expression of TOPK was significantly correlated with Ki67 LI (P<0.01) and TP53 expression level (P<0.01). Meanwhile, the TP53 expression level was also significantly correlated with the Ki67 LI (P <0.01). Moreover, EGFR expression in IDH1‐positive group was significantly higher than in IDH1‐negative group and significant correlation between TOPK and TP53 expression was found in HGG‐IDH1+ group. However, in LGG, higher expression levels of c‐myc (P<0.05) and Ki67 LI (P<0.05) were observed in IDH1+ group, than in IDH1‐.

Conclusions: Our results suggest that TOPK could be a novel and independent parameter, helpful to assess the behavior of adult malignant glioma, and may associated with TP53‐related signal‐pathways, but not IDH1 mutations. Key Words: glioma TOPK TP53 IDH1 immunohistochemistry pathology

P3‐12

Gliomas 1p/19q codeleted, p53 mutated and EGFR amplified. Are they mixed gliomas?

Naomi Arakaki; Gustavo Sevlever; Paulina Yanez; Florencia Cora; Blanca Diez; Sebastian Cerrato; Marcelo Schultz; Horacio Martinetto

Department of neuropathology FLENI

Introduction: Gliomas are the most frequent intrinsic brain tumors. The recurrent mutation in isocitrate dehydrogenase 1 and 2 genes (IDH1/IDH2) allowed to split gliomas into IDH mutant and IDH wild type mega‐groups, the latter having less favorable course. Molecular markers were incorporated in the 2016 WHO update classification for diffuse gliomas. Accordingly, Oligodendroglioma (OD) is now defined by the simultaneous presence of IDH mutation and 1p‐19q codeletion while Astrocytoma (A) is characterized by IDH mutation without the codeletion and usually harbors P53 and ATRX mutations.

Methods: Molecular Institutional data base revealed 10 adult patients from a total of 105 IDH mutated tumors which presented 1p‐19q codeletion together with EGFR trisomy and/or mutant TP53.

Results: Histologically the honeycomb appearance was present in 8 cases (c), and 2c without perinuclear halos, had astrocytic like elements. Inmunohistochemical study revealed ATRX retained label 5c, partially retained 3c and negative 1c reflecting mutation. Ki67 proliferation index showed mean value 9%. RT‐PCR findings: codeletion 1p/ 19q, was detected in 10 c, 3x amplification EGFR in 8c, IDH1 mutation in 8c, IDH2 mutation in 2c and P53 mutation in 4c. A statistically significant difference in overall survival (OS) was detected when comparing this small group to OD (p=0.0115) but not to A ( p=0.2148) log‐rank test.

Discussion: According to the WHO classification the analyzed group should be defined as OD, but molecular aspects, OS, KI67 do not reflect the typical characteristics. These results raise the question about the existence of olygoastrocytoma.

P3‐13

Do gemistocytic astrocytomas really exist? The longstanding debate about gemistocytes present in diffuse gliomas may be solved

Aline H. S. Camacho^1,2; Debora Silva¹; Diego De Araujo Santos¹; Leila Chimelli¹

¹Laboratorio de Neuropatologia e Genetica, Instituto Estadual do Cerebro Paulo Niemeyer; ²Divisao de Anatomia Patologica, Instituto Nacional do Cancer

Introduction: The classification of diffuse gliomas established by the World Health Organization (WHO) has always been a matter of debate, with frequent inter observer disagreement. Recently, neuropathologists in charge of elaborating the 2016 classification have established criteria to make it more precise, incorporating molecular information, in particular the ATRX loss to differentiate astrocytomas from oligodendrogliomas. However, the practice shows that there are still controversial cases, including the fact that ATRX loss is not observed in gemistocytes present in diffuse gliomas. In addition, as already known, gemistocytes do not proliferate. Immunoreaction with KI67 is only seen in intermingled IDH1 positive cells with larger nuclei and scant cytoplasm. Considering the fact that gemistocytes are also negative or weakly positive with IDH1R132H, we postulate that the background rich in gemistocytes is reactive. To investigate this we performed double staining (ATRX/GFAP) in a series of gemistocytic astrocytomas.

Methods: We analyzed 120 diffuse gliomas from 2013 to 2018 of patients that at the time of diagnosis were older than 18 years. We selected 20 cases rich in gemistocytes and performed double stainings with immunohistochemistry, using GFAP (red chromogen) and ATRX (brown chromogen).

Results: In all cases most gemistocytes were ATRX positive and many involved ATRX negative neoplastic cells with bare nuclei.

Conclusion: The gemistocytic astrocytoma, which is known to have a more aggressive behavior, probably shows in its gemistocytic component, a reactional pattern, serving as a framework of growth modulators for the proliferation of neoplastic glial cells.

P3‐14

A case of epithelioid glioblastoma; unusual presentation of a rare tumour with full biomarker assessment

John P Provias¹; C. Hawkins²; O. Ajani³; A. Fleming⁴

¹Department of Pathology & Molecular Medicine, McMaster University, Hamilton Health Sciences, Hamilton General Site; ²Department of Pathology, University of Toronto; ³Pediatric Neurosurgery, McMaster University; ⁴Pediatric Hematology/Oncology, McMaster University

Introduction: Epithelioid glioblastoma is a rare type of glioblastoma occurring in younger patients predominantly. We present an informative case presenting as an extra‐axial tumour, in many respects mimicking meningioma, with molecular biomarker assessment.

Clinical summary: The patient was a 17‐year‐old female university student who was previously well. She presented with a few month history of headaches and intermittent “blackout spells” lasting 2‐3 minutes each. There was no relevant family history. MRI investigation showed a left parieto‐temporal dural based extra‐axial enhancing tumour mass, thought to be most consistent with a meningioma. The patient underwent a “gross total type resection”.

Pathological findings: Neuropathologic examination showed a cellular neoplasm with areas of prominent epithelioid and rhabdoid type morphology. Tumour growth focally into the meninges and dura was evident. There was abundant mitotic activity as well as areas of palisading tumour necrosis and focal microvascular proliferation. A summary of the extensive immunohistochemical and biomarker profile showed epithelial membrane antigen, STAT6 and p53 to be negative. The tumour was positive for OLIG2 and focally positive for glial fibrillary acidic protein. Biomarker assessment showed the presence of BRAF V600E point mutation.

Conclusion: We present a rare case of an epithelioid glioblastoma presenting as an extra‐axial dural based tumour. Given the superficial hemispheric growth of typical epithelioid glioblastomas, this presentation may be more common than realized and, with the rhabdoid type morphology, can easily be confused with rhabdoid meningioma. Immunohistochemistry for EMA, OLIG2, as well as BRAF V600 mutational testing, are useful for diagnostic assessment.

P3‐15

Adenocarcinoma arising in neurenteric cyst in the 4th ventricle mimicking choroid plexus carcinoma: A case report and literature review

Seonghye Choi¹; Yangki Minn²; Yoon Jin Cha³

¹Department of Neurology, Inha University College of Medicine, Inha Hospital, Incheon, Korea; ²Department of Neurology, Hallym Univeristy College of Medicine, Kangnam Sacred Heart Hospital, Seoul, Korea; ³Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea

Introduction: Neurenteric cysts are rare, and most commonly located in the subarachnoid space anterior to the cervical spinal cord. Malignant transformation of neurenteric cyst is an exceedingly rare complication. Here, we report a rare case of adenocarcinoma arising from the neurenteric cyst in the 4th ventricle, which clinically and radiologically mimicked choroid plexus carcinoma (CPC).

Clinical summary: A 41‐year‐old female patient without specific medical history presented with persisting headache and nausea for a month. Brain magnetic resonance image (MRI) revealed a 3.7 cm‐sized, enhancing cauliflower‐like mass with cystic portion in right lateral ventricle with hydrocephalus with additional 2.2cm‐sized non‐enhancing mass in the left foramen magnum. Suspicion of choroid plexus papilloma with seeding tumor nodule, gross total removal of tumor was performed. Patient went into a coma with diffuse cerebral dysfunction and died 5 months after the surgery.

Pathologic findings: At low power view, tumor had papillary growth pattern and brain invasion. Tumor cells were overtly malignant, consistent with carcinoma. In addition, cyst component composed of flat to stratified ciliated bland‐looking epithelium was observed. Differential diagnoses included CPC, metastatic carcinoma from elsewhere, and malignant transformation of pre‐existing neurenteric cyst. On immunohistochemistry, tumor cells were positive for CK and CDX2 (focal), and negative for TTF‐1, PAX8, WT1, synaptophysin, GFAP. Taken together, diagnosis of adenocarcinoma arising from neurenteric cyst was rendered.

Conclusion: Although rare, carcinoma arising from the neurenteric cyst within the ventricle can mimic CPC. Pre‐existing benign cyst component and exclusion of metastatic carcinoma is important to make an accurate diagnosis.

P3‐16

Detection of ALK and EGFR gene mutation in non‐small cell lung adenocarcinoma with brain metastases and its correlation with clinicopathological features

Luning Mao¹; Chenyue Xu¹; Ji Xiong²; Yin Wang²; Xin Wang³; Ying Liu¹

¹Department of Pathology, School of Basic Medical Science, Fudan Univeristy; ²Department of Pathology, Huashan Hospital, Fudan University; ³Department of Neurosurgery, Huashan Hospital, Fudan University

Objective: To analyze the pathological features of brain metastases in lung adenocarcinoma and the changes of ALK and EGFR genes, and to guide the treatment of patients with advanced lung cancer.

Methods: From 2013 to 2016, a total of 74 patients with brain metastatic lung adenocarcinoma were enrolled in this study. Paraffin sections were stained with HE for pathological analysis, and using immunohistochemical method to detect Ki‐67, ALK and EGFR gene.

Results: All specimens were invasive adenocarcinoma, and were solid (59.46%), acinar (12.16%), papillary (19.7%), micropapillary (18.42%), there are significant differences between brain metastatic lung adenocarcinoma and primary lung adenocarcinoma(P<0.01). The average Ki‐67 expression rate of solid, acinar, papillary, micropapillary was signigicantly different(P<0.05) . Total expression of ALK gene and EGFR gene were detected in 7 cases(9.46%) and 39 cases(52.70%) respectively. Group of ALK gene high expression had the average tumor necrosis rate of 7.14±2.75%, while the low expression group was 20.15±4.92% (P<0.01), group of Ki‐67 high expression of ALK gene was 15.00±2.76%, while the low expression group was 26.31±4.70% (P< 0.01).

Conclusion: There was a significant difference in pathologic subtype distribution between brain metastatic lung adenocarcinoma and primary lung adenocarcinoma. Tumor cell proliferation was closely related to pathologic subtype. The expression rates of ALK and EGFR genes in brain metastases were consistent with those of primary lung adenocarcinoma, and the expression levels of ALK and EGFR genes were mutually exclusive.

P3‐17

Intramedullary spinal cord angiolipoma

Arunee Singhsnaeh¹; T. Panyaping²; A. Boongird³; Lee Cyn Ang⁴

¹Department of Pathhology, Faculty of Medicine, Mahidol University, Thailand; ²Department of Radiology, Faculty of Medicine, Mahidol University, Thailand; ³Department of Surgery, Faculty of Medicine, Mahidol University, Thailand; ⁴Department of Pathology and Laboratory Medicines, London Health Sciences Center, Ontario, Canada

Introduction: Spinal cord angiolipomas are rare benign lesions accounting for approximately 0.1‐0.5% of all spinal cord tumours and are represented in the literature as scattered, single case reports. Although most spinal angiolipomas are epidural tumours, a small proportion can be intramedullary. The usual clinical presentation includes back pain, and progressive numbness and weakness of the limbs.

Clinical Summary: We report a case of a 47‐year‐ old woman who presented with symptoms of decrease sensation of left arm and right leg, and difficulties in raising left shoulder. Patient has no evidence of spinal dysraphism. The MRI shows a small well‐defined intense enhancing intramedullary nodule in the left sided posterior cord at C4 level and shows associated syringohydromyelia extending from medulla oblongata down to C4‐C5 level. The pre‐operative differential diagnoses included cystic astrocytoma, ependymoma and hemangioblastoma. The patient underwent surgery with total resection of the lesion. The gross section during intraoperative consultation shows a well‐defined red brownish nodule.

Patholigical findings: The histopathological examination reveals mainly matured adipocytes with scattered intervening small vessels. There is no evidence of malignancy. The histopathological diagnosis is compatible with an intramedullary angiolipoma. Her clinical symptoms subsequently improved after surgery.

Conclusion: Although, intramedullary angiolipoma is rare but it represents a potentially curable condition, and should therefore be considered in the differential diagnosis of primary intra‐axial tumors in adults.

P3‐18

Diffuse leptomeningeal glioneuronal tumor exhibiting 1p/19q co‐deletion and H3F3K27M mutation: A rare case with unique molecular profile

Kavneet Kaur; Aruna Nambirajan; Prit Benny Malgulwar; Vaishali Suri; Mehar Chand Sharma; Ajay Garg; Chitra Sarkar

All India Institute of Medical Sciences (AIIMS), New Delhi

Introduction: Diffuse leptomeningeal glioneuronal tumour is a new entity in the recent WHO classification of CNS tumors (2016). It is a rare tumour characterised by predominant and widespread involvement of leptomeninges with olidodendroglial like cytology. Most are low grade, a small proportion show aggressive behaviour. Hence, a definite WHO grade is not yet assigned.

Clinical Summary: A 13‐year‐old female child presented with complaints of diminution of vision in both the eyes and headache for 1 year and paraplegia with bladder and bowel dysfunction for 1 month. MRI revealed an intadural extramedullary mass in D1‐D4 region of spinal cord and multiple T2 hyperintense lesions in sulcal spaces of cerebellum, choroid plexus of lateral ventricles, putamina and pons.

Pathological findings: Biopsy from a mass in the conus region showed a tumour with oligodendroglia like cytology and glomeruloid vessls with moderately high MIB1 index. The tumour cells were immunopositive for GFAP, synaptophysin, NeuN while negative for IDH and showed retained ATRX expression. The tumor was found to harbour 1p/19q co‐deletion by Fluorescence in‐situ hybridisation and H3F3A mutation by Sanger‐sequencing. IDH mutations and BRAF alterations were not found by sequencing and RT‐PCR, respectively. Based on overall findings, a diagnosis of diffuse leptomeningeal glioneuronal tumour was rendered.

Conclusions: Diffuse leptomeningeal glioneuronal tumors represent a distinct clinico‐pathological entity. Even though histologically benign, they can show aggressive behavior due to involvement of wide area of leptomeninges, development around the brainstem and difficulty in surgical intervention. Hence, a knowledge of this new entity is imperative to arrive at the correct diagnosis.

P3‐19

Expression of collagen VI, laminin, MMP9, anticollagenase, claudins 1 and 5, N and E cadherins in choroid plexus tumors

Martha Lilia Tena‐Suck¹; Francisca Fernandez‐Valderde²; Daniel Rembao‐Bojorquez¹; Citlaltepetl Salina‐Lara¹; Carlos Sanchez‐Garibay¹

¹Department of Neuropathology, National Institute of Neurology and Neurosurgery; ²Experimental laboratory of Neurotheology. National Institute of Neurology and Neurosurgery

Introduction: The Choroid plexus tumor(CPT) are an uncommon tumor derived from choroid plexus epithelial cells (CPECs), that are seen predominantly in children than adults. CPECs are closely connected to each other by tight junctions and establish the structural basis of the blood‐CSF barrier.

Methods: The immunohistochemical expression of Claudin 1, and 5, E and N cadherin, laminin, and anticollagenase, basement membrane component type IV collagen and proliferation of Ki67‐li and MVD‐li were investigated in 42 choroid plexus tumors. Clinical pathological, immunohistochemical and ultrastructure correlations.

Results: 28(67%) were choroid plexus papillomas(CPP), 8(19%) were atypical choroid plexus papillomas(ACPP) and 6 (14%) choroid plexus carcinomas(CPC). 37 were female (62%9) and 23 males (42%). Tumor localization; supratentorial portion were 35(58%), and infratentorial region in 25(42%), 11(18%) were located in lateral ventricles, 6(10%) in III ventricle and 25(42%) in IV ventricle. The Ki67‐li and MVD increased from CPC to ACPP, being the highest in malignant tumors as well as a strong immunoexpression of anticollagenase and were inverse correlation with claudin 5, E and N cadherin and collagen IV membrane basal immunohistochemical expression which added further significant information to the prognosis and varied according to the histologic classification. By ultrastructure the loss of membrane basal was observed in CPC.

Conclusions: The loss of membrane basal and over expression of extracellular matrix could be considered as predictor factor in CPT as bad prognosis in CPT. Anticollagenase, MMP9 overexpression could be in relationship with basal membrane and BBB plasticity in CPTs.

P3‐20

A case of high‐grade glioma simulating epithelioid glioblastoma

Katsushi Taomoto¹; Kazuhiko Nishioka¹; Yuji Kodama¹; Yoshihiro Kuga¹; Hideyuki Ohnishi¹; Takanori Hirose²

¹Department of Neurosurgery, Ohnishi Medical Center, Akashi, Hyogo, Japan; ²Department of Diagnostic Pathology, Hyogo Cancer Center

Introduction: Epithelioid glioblastoma (EG) is a rare, recently recognized variant of glioblastoma composed of epithelioid and rhabdoid tumor cells. We herein reported a case of high‐grade glioma simulating EG.

Case Report: A 47‐year‐old female visited a neurosurgical clinic, because of headache, which continued for 2 weeks and increased its intensity. She also complained of vomiting and misty vision. As a brain tumor was pointed out by MRI, she was referred to our hospital. No neurological symptoms other than headache and choked disc were present at admission. A tumor of 6cm in diameter, associated with cysts and calcification, was located in the right temporal lobe. DSA showed a light tumor shadow and the feeding arteries were the right posterior cerebral artery and the anterior and posterior temporal arteries. With the right subtemporal approach, the tumor was gross‐totally excised, and the postoperative course was uneventful with radiation and temozolomide combination therapy.

Pathologic findings: Microscopically, the tumor was composed of a sheet‐like growth of epithelioid tumor cells with ovoid nuclei and eosinophilic cytoplasm, associated with calcification and hemorrhage. Mitotic figures, necrotic areas, and microvascular proliferation were noted. Immunohistochemically, tumor cells were positive for GFAP and p53, but negative for EMA, CD34, IDH1 R132H, and BRAF V600E. Ki‐67 labeling index was 15%. 1p/19q codeletion was not detected by FISH.

Conclusion: About a half of EG are known to have BRAF V600E mutation. Although the mutation was not present, the pathologic findings of the present tumor were similar to those of EG.

P3‐21

A poor prognostic case of pediatric glioblastoma with IDH1 mutation

Kanako Kawanami¹; Kenichiro Matsuda¹; Rintaro Ooe²; Mitsunori Yamakawa²; Yukihiko Sonoda¹

¹Department of Neurosurgery, Faculty of Medicine, Yamagata University; ²Department of Pathological diagnosis, Faculty of Medicine, Yamagata University

Introduction: Isocitrate dehydrogenase 1 (IDH1) mutation was found in 5‐10 % of adult glioblastoma (GBM) patients. However, only few papers reported the cases of pediatric GBM with IDH mutation. Here, we report a rare case of pediatric glioblastoma with IDH1 mutation.

Case: A‐11‐year‐old female with a progressive right upper limb paralysis and motor aphasia admitted to our hospital. MR imaging revealed a ring‐shaped contrast lesion in the left frontal lobe. The patient underwent surgery and post‐operative MRI imaging showed subtotal resection of the tumor. Histopathological examination showed both microvascular proliferation and necrosis. Immunohistochemical staining revealed a negative of MGMT, and a positive of p53. The Ki‐67 labeling index was 30%. The IDH1 (R132H) specific antibody was positive and it was confirmed by Sanger sequencing. The final diagnosis was GBM with IDH mutation. Following after surgery, she received radiation therapy concurrent with temozolomide. However, the tumor was recurred during radio‐chemotherapy, then we performed 2nd surgery. Four months after 2nd surgery, the tumor enlarged again, she underwent 3rd surgery. Despite of bevacizumab treatment and intrathecal injection of methotrexate, it was difficult to control tumor growth. The patient was dead by disease 11 months after initial therapy.

Discussion: Korshunov et al. reported in 202 cases of pediatric GBM, IDH1 mutation was found in only 10 cases (4.9%). These cases had relatively good prognosis and 3 years overall survival rate was 90%. In contrast, our case was refractory to any treatment and showed poor prognosis.

P3‐22

An elderly case of anaplastic pleomorphic xanthoastrocytoma

Nobuko Ujihira¹; Michihiko Narita¹; Eiji Tachibana²; Atsushi Sasaki³

¹Department of Pathology, Toyota Kosei Hospital; ²Department of Neurosurgery, Toyota Kosei Hospital; ³Department of Pathology, Saitama Medical University

Pleomorphic xanthoastrocytoma (PXA) is WHO grade II astrocytoma, mainly situated in the superficial regions of the temporal lobe in child and young adult. PXA with more than 5 mitoses per 10 high‐power‐fields was defined anaplastic pleomorphic xanthoastrocytoma (APXA) in 4th WHO classification, grade III. We report an elderly case of APXA.

Case: A 77‐year‐old‐man PH:HT, DM, Depression and renal cancerPI: The patient showed progressive hemiparesis in the right for 10 months before visiting our hospital. MRI revealed enhanced mass lesion in the left frontal lobe without cystic component. Subtotal tumor resection was performed.

Pathological findings: In histopathological examination, tumor cells showed pleomorphism. Spindle cells, small roud cells, giant cells were intermingled, proliferation of ganglion cells were found. Eosinophilic granular bodies were seen. Necrosis was not present. Microvascular proliferation was noted. Mitoses : 13/10HPF. Tumor cells were surrounded by reticulin fibers. In the immunohistochemical staining, tumor cells were positive in GFAP. Ki67 LI : 20%. BRAF V600E mutation was detected. IDH1, IDH2, H3F3A and TERT were wild type, We diagnosed APXA.

Summary: Elderly patients with APXA are rare, although the age of onset in APXA is older than PXA. Only 17 APXA patients more than 60‐year‐old have been reported. Tumors were situated in the temporal lobe in 7cases of the 17 elderly onset APXA. The frequency of BRAF V600E mutation is lower among APXA than among WHO grade II PXA. We report a rare case of elderly APXA with BRAF V600E mutation.

P3‐23

Mitogen‐activated protein kinase in gliosis and pilocytic astrocytoma

Hiroaki Takeuchi¹; Makoto Isozaki¹; Kazuhiko Yoshida¹; Takahiro Yamauchi²; Ryuhei Kitai²; Ken‐ichiro Kikuta²

¹Department of Neurosurgery, Tan‐nan Regional Medical Center; ²Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui

Pilocytic astrocytoma (PA), featuring activation of the mitogen‐activated protein kinase (MAPK) pathway, is the most common tumor of the pediatric central nervous system. However, it remains unknown whether MAPK activation is present in the reactive gliosis of non‐neoplastic lesions. Therefore, we investigated the expression of MAPK in reactive gliosis associated with cavernous angiomas. Immunohistochemical expression and the extent of BRAF, ERK, p38, and JNK were investigated in ten patients with gliosis surrounding cavernous angiomas (GS group) and ten patients with PA (PA group). Evaluation of these parameters was scored as 0, none; 1, scarce; 2, moderate; 3, global. In GS group, histopathologic features of PA included piloid cells, Rosenthal fibers, microcysts with eosinophilic granular bodies were identified. Expression of ERK, and p38 was shown in all patients in GS and PA groups. Expression of BRAF was identified in five patients (50%) in the GS group and in eight (80%) in the PA groups. The mean score of BRAF expression in the PA group was significantly higher than that in the GS group (p=0.019). Reactive gliosis may resemble PA in histological findings and MAPK activation. Therefore, PA could be indistinguishable from reactive gliosis with classic histopathologic and/or immunohistochemical methods.

P3‐24

Efficacy of ICE plus Bevacizumab Therapy for Temozolomide‐Resistant Anaplastic Astroblastoma: Case Report

Kiyotaka Saito¹; Shinji Yamashita¹; Tomoki Kawano¹; Takahiro Yokoyama¹; Tsuyoshi Fukushima²; Kiyotaka Yokogami¹; Hideo Takeshima¹

¹Department of Neurosurgery, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Japan; ²Department of Oncopathology and Regenerative Biology, Division of Pathology, Faculty of Medicine, University of Miyazaki, Japan

We recently encountered a case of anaplastic astroblastoma with temozolomide (TMZ) resistance in which ICE plus bevacizumab (Bev) therapy was effective. This 41‐year‐old man presented with headache, nausea, speech difficulty, and complex partial seizures. MRI demonstrated an intraaxial mass in the left frontal lobe (about 7‐cm diameter) with clear boundaries. Surgery was performed and postoperative MRI confirmed gross‐total tumor resection. Postoperative histopathological examination revealed anaplastic astroblastoma. The patient underwent TMZ chemotherapy with 60 Gy radiation therapy and was discharged from our hospital. Seven months later, after five courses of TMZ maintenance therapy, he presented with systemic convulsion. MRI demonstrated multiple tumor masses on the dura mater of the clivus and the occipital lesion, and the whole spine. These findings were strongly suspected to indicate dural metastasis and CSF dissemination of the anaplastic astroblastoma. After a multidisciplinary discussion, ICE + Bev therapy was begun. After the second‐line chemotherapy, the tumors remained well controlled for some months, but finally became uncontrollable and the patient died at 11 months after the diagnosis of tumor recurrence. Based on our experience, ICE plus Bev therapy is effective as second‐line therapy for anaplastic astroblastoma.

P3‐25

A case of radiation‐induced sarcomas 10 years after radiation therapy against glioblastoma

Takeo Uzuka; Hadzuki Matsuda; Fumi Higuchi; Phyo Kim; Keisuke Ueki

Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan

We report a case of radiation‐induced sarcomas 10 years after radiation therapy against glioblastoma. A 61‐year‐old man was referred to our department because a brain tumor recurrence was suspected in the MR images. He had underwent left frontal tumor resection 10 years ago, and received radiotherapy (extended‐local, 60Gy/30fr) and temozolomide chemotherapy. The tumor was recognized as enhancing nodules of the resected cavity wall on MR images. Some nodules taken by the resection surgery were diagnosed as osteosarcoma, and other nodules were recognized as rhabdomyosarcoma. There were no features of glioblastomas in all nodules. These two types of sarcomas were considered as radiation‐induced tumors, even though such case is extremely rare.

P3‐26

Anti‐tumor effects of metformin against malignant glioma

Satoshi Suzuki; Reika Kitagawa; Toru Iwaki

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

An antidiabetic drug metformin is known to have anti‐tumor effects. We herein studied the mechanism of anti‐tumor effects of metformin in glioma cells. We cultured a human glioma cell line U373MG in a medium with low‐serum/low‐glucose concentrations to optimize the effects of metformin. Then, we investigated the altered expression patterns of lipid metabolism‐associated proteins after metformin treatment by immunoblotting and immunofluoresence. We also carried out microarray gene expression analysis after metformin treatment. We found that 1) metformin strongly inhibited proliferation of the glioma cells; 2) Metformin promoted phosphorylation of AMP‐activated protein kinase (AMPK) and downregulated fatty acid synthase (FASN) and acetyl‐CoA carboxylase α (ACACA). In addition, ACACA was phosphorylated (inactivated), and translocated from the cytoplasm to the nucleus; 3) metformin upregulated 58 tumor suppressor genes. These findings suggest that in U373MG, metformin activates AMPK followed by phosphorylation and inactivation of ACACA as well as downregulation of FASN, resulting in inhibition of fatty acid synthesis and cell proliferation. Furthermore, metformin upregulated various tumor suppressor genes at the transcription levels. It is possible that metformin inhibits tumor growth through epigenetic modification of these tumor suppressor genes. We conclude that metformin exerts its anti‐tumor effects in a multifaceted fashion.

P3‐27

Heterogeneous clinico‐pathological features of diffuse midline glioma H3‐K27M mutant

Yuma Okamura¹; Keiichi Kobayashi¹; Kuniaki Saito¹; Daisuke Shimada¹; Shinya Suematsu¹; Tomohiro Chiba²; Junji Shibahara²; Saki Shimizu¹; Yoshiaki Shiokawa¹; Motoo Nagane¹

¹Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan; ²Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan

A specific lysin to methionine mutation (K27M) in histone variants H3.3 or H3.1 has been identified predominantly in diffuse infiltrative midline gliomas, and defined as a new glioma entity of grade IV malignancy in WHO Classification Criteria 2016 update. However, there remains a controversy whether harboring H3‐K27M mutation is inevitably associated with a specific pathology showing unfavorable outcome or not. Here we present our recent experience of five patients with glial tumors diagnosed as DMG H3‐K27M since 2016 in our institution. Representative cases: Case 1: 60 yo female, with a large non‐enhancing thalamic mass; anaplastic astrocytic tumor with a high Ki‐67 index (30%). She received radiotherapy (RT) and temozolomide (TMZ) but had recurrence 12.6 m later. Case 2: 29 yo female, with a non‐enhancing pontine and enhancing cerebellar lesions. Glioblastoma‐like tumor had a high Ki‐67 index (40%). She received RT/TMZ followed by TMZ/bevacizumab (BEV), with PFS 10.4 m and OS 15.3 m. Case 3: 31 yo male, with a large enhancing mass with calcification and cysts in the cerebellum with EGFR amplification. He was treated with Stupp regimen without progression (15.1 m). Case 5: 36 yo male, with a huge non‐enhancing mass involving bilateral cerebral hemisphere with a spot enhancing lesion. He was treated with RT/TMZ with response. These 5 cases illustrated glial tumors with common H3‐K27M mutation without IDH mutation but associated with distinct spatial distribution, imaging characteristics, and response to treatment. The detailed features will be presented with potential classification of K27M tumors.

P3‐28

An autopsy case of diffuse midline glioma around the foramen of Monro

Masako Ikemura^1,2; Atsushi Kondo²; Hiroyuki Abe²; Tetsuo Ushiku²; Shunsaku Takayanagi³; Masahiro Shin³; Shota Tanaka³; Masashi Fukayama^1,2

¹Promotion office of CPC Education and General Integrative Medicine, University of Tokyo; ²Department of Pathology, University of Tokyo; ³Department of Neurosurgery, University of Tokyo

Introduction: Diffuse midline glioma with histone H3‐K27M mutation is a new tumor entity defined by the 2016 WHO Classification of Tumors of the Central Nervous System. Several studies using biopsy or surgical specimens reported that the pathological features of diffuse midline glioma are highly variable, ranging from WHO grade I ‐like to Grade IV‐like. We herein report an autopsy case of diffuse midline glioma.

Case: A 43‐year‐old woman presented with headache and cognitive decline. Head CT revealed a tumor around the right foramen of Monro. Histologically, this tumor diagnosed as a high grade glioma based on high Ki‐67 expression and the presence of the histone H3 K27M mutation, despite low grade glioma‐like morphology. The patient was treated with combination therapy of radiotherapy and chemotherapy, but died three years after the initial presentation. An autopsy revealed a right basal ganglia glioma with subarachnoid spread and invasion in the corpus callosum. Histologically, the tumor showed high grade morphological features with necrosis and microvascular proliferation. In a small area, low grade morphological features were found similar to the initial biopsy.

Conclusion: This autopsy case revealed marked histologic intratumoral heterogeneity of diffuse midline glioma. For accurate pathological diagnosis, it is important to perform biopsy from the appropriate site and to keep in mind that most of diffuse midline glioma show marked intratumoral heterogeneity.

P3‐29

Imaging and immunohistochemical characteristics of H3 G34R‐mutant gliomas ‐a report of three cases‐

Shumpei Onishi^1,2; Fumiyuki Yamasaki¹; Takeshi Takayasu¹; Motoki Takano¹; Ushio Yonezawa¹; Vishwa Jeet Amatya³; Yukio Takeshima³; Kazuhiko Sugiyama⁴; Kaoru Kurisu¹

¹Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; ²Department of Neurosurgery, Higashihiroshima Medical Center, Hiroshima, Japan; ³Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; ⁴Department of Clinical Oncology and Neuro‐oncology Program, Hiroshima University Hospital, Hiroshima, Japan

The K27M mutation in histone H3.3 (H3F3A) and H3.1 (HIST1H3B/C) are defined as a new entity and named ‘diffuse midline glioma, H3 K27M‐mutant’ in WHO 2016 update. The G34 mutations, on the other hand, are found predominantly in supratentorial non‐midline tumors and are not categorized as a new entity yet. We report the immunohistochemical and imaging characteristics of this rare tumor. Case 1: A 13‐year‐old. MRI showed non‐enhancing left frontal tumor with intratumoral hemorrhage and was hyper‐intense on diffusion‐weighted imaging (DWI). The tumor was excised in toto and was histologically diagnosed as glioblastoma based on 2007 WHO classification. Case 2: A 19‐year‐old female. MRI revealed a right parietal tumor with partial enhancement and slight hyper‐intensity on DWI. The tumor was completely excised and was histologically diagnosed as anaplastic astrocytoma based on 2007 WHO classification. Case 3: 15 year‐old female. MRI revealed a right fronto‐parietal tumor with partial enhancement and hyper‐intensity on DWI. The tumor was partially excised and was histologically diagnosed as PNET based on 2007 WHO classification. In these cases, the tumor cells were immunoreactive to H3 G34R‐mutant and p53 antibodies, and non‐reactive to H3 K27M‐mutant, IDH1‐R132H, ATRX, and olig2. Immunohistochemical characteristics are valuable for predicting the mutation of H3 G34R in pediatric, adolescents and young adult gliomas. Negativity to olig2 may be the characteristic of H3 G34R‐mutant gliomas. DWI hyper‐intensity reflects the tumor cellularity and may be associated with malignant grade of H3 G34R‐mutant gliomas.

P3‐30

Histopathological analysis of the new mouse glioma model which shows perineural invasion

Masafumi Miyai^1,2; Hiroyuki Tomita²; Tomohiro Kanayama²; Tetsuya Yamada¹; Noriyuki Nakayama¹; Naoyuki Ohe¹; Hirohito Yano¹; Akira Hara²; Toru Iwama¹

¹Department of Neurosurgery, Gifu University Graduate School of Medicine; ²Department of Tumor Pathology Gifu University Graduate School of Medicine

The treatment to diffuse invasion of glioma is difficult. Now, there is little effective treatment to diffuse invasion of glioma. We produced the new mouse glioma model which shows perineural invasion. We compared the feature of both histopathological for the mouse glioma model used conventionally. We investigated the proliferation potency of a mouse glial cell line with Histone 3.3 K27M mutation. We transfected Histone 3.3 K27M mutant into the mouse glial cell(K27M cell). The expression level of the cell line was confirmed by real‐time RT‐PCR and immunofluorescence with antibodies. In vitro, we performed co‐culture, K27M mutant mouse glioma cell and primary neuronal cells. We demonstrated the active tumor cell motion by time lapse photography. In vivo, we transplanted K27M cell or GL261 cell to the nude mouse brain(N=5). Cells were injected (5.0×10^5 cells/µl) into the right striatum. GL261 model proliferated in distensibility. Furthermore the border of this model was clear. By contrast, K27M cell model proliferated diffuse invasion. The border of this model wasn't clear. Furthermore we demonstrated much perineural invasion. We established the new mouse glioma model which shows perineural invasion. This model leads to elucidation of the mechanism of the perineuronal invasion for diffuse glioma.

P3‐31

A case of anaplastic astrocytoma with appearance of IDH‐mutant astrocytic cells at recurrence

Noriaki Sakamoto^1,2; Eiichi Ishikawa¹; Kazuki Sakakura¹; Takaaki Ishikawa¹; Shingo Sakashita²; Masayuki Noguchi²; Akira Matsumura¹

¹Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; ²Department of Diagnostic pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

We report a 57‐year‐old man who had a brain tumor in right front‐temporal lobe. MRI showed a high intensity area in T2WI without contrast‐enhanced lesion. Then the tumor was slowly growing and appeared with contrast‐enhanced lesion. This patient underwent craniotomy and gross‐total resection was done. This tumor was diagnosed histologically anaplastic astrocytoma, WHO grade III and immunohistochemically showed IDH1R132H‐negative, ATRX‐loss, p53‐mutant. The patient received TMZ‐based chemoradiotherapy postoperatively. 8‐months later, MRI showed a local recurrence with contrast‐enhanced lesion. The patient received second craniotomy and removed the lesion. The resected lesion showed necrotic brain tissue by radiotherapy. However small amount of atypical astrocytic cells were seen and they showed IDH1R132H‐positivity immunohistochemically. After that, the lesion tended to growing, we think this was residual/recurrent tumor. This is so problematic case, because status of IDH‐mutation doesn't change according to current WHO 2016. We want to discuss this case.

P3‐32

Cerebellar radiation‐induced glioma after complete remission of pineal tumor

Tomohiro Kawano¹; Takashi Watanabe²; Kiyotaka Yokogami²; Tsuyoshi Fukushima³; Hideaki Yokoo⁴; Hideo Takeshima²

¹Department of Neurosurgery, Wada Hospital, Miyazaki, Japan; ²Department of Neurosurgery, University of Miyazaki, Japan; ³Department of Oncopathology and Regenerative Biology, Division of Pathology, Faculty of medicine, University of Miyazaki, Japan; ⁴Department of Human Pathology, Gunma University Graduate School of Medicine, Japan

Background: Histopathological diagnosis of radiation‐induced glioma (RIG) is difficult in many cases as there remains a lack of reliable biomarkers.

Case Description: A 10 year‐old boy was diagnosed as a pineal tumor based on the neuro‐imaging and achieved complete remission after radiation therapy with 49 Gy (whole brain: 21 Gy, focal: 28 Gy). Follow‐up MR imaging showed no recurrence during more than 30 years. He presented with gait disturbance due to progressive right cerebellar ataxia 31 years after the irradiation (at age 41 years). MR imaging demonstrated ring‐like enhanced lesion without perifocal edema in the left superior cerebellum, rapidly growing over 5 months. The tumor was gross totally removed via occipital transtentorial approach. Histological examinations showed diffuse proliferation of atypical tumor cells and invasion into the cerebellar parenchyma, however apparent pseudopalisading necrosis and microvascular proliferation could not be identified. Immunohistochemical examinations revealed phenotypes of the tumor cells as follows; GFAP (+), INI‐1 loss (‐), ATRX (nuclear alpha thalassemia/mental retardation syndrome X‐linked) loss (‐), isocitrate dehydrogenase1 (IDH1)‐R132H (‐). The MIB‐1 labeling index was up to 59%. Direct DNA sequencing analysis showed no mutations of IDH1, IDH2, telomerase reverse transcriptase (TERT) promoter, H3F3A, HIST1H3B and BRAF.

Conclusion: Negative findings of the molecular biomarkers for conventional gliomas might provide important and helpful information on pathological diagnosis of RIG, especially in cases with unknown histological diagnosis of the primary lesions.

P3‐33

Consideration of integrated diagnosis of gliomas

Kaoru Ogawa¹; Akihisa Kamataki¹; Akira Kurose¹; Noriko Kato¹; Kenichiro Asano¹

¹Department of Anatomic Pathology Hirosaki University Graduate School of Medicine, Aomori, Japan; ²Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan

Genetic status of IDH, ATRX, BRAF, H3K27M and 1p/19q should be incorporated to make integrated diagnosis according to the revised WHO classification in 2016. Here, we compared between histological and integrated diagnosis of astrocytomas (A), oligodendrogliomas (O), oligoastrocytomas (OA) and glioblastomas (GBM) operated at our hospital since 2016. As a result, histological diagnosis and integrated diagnosis were largely correlated. All cases of histological A were proven to be integrated diagnosis of A. Some cases of histological O were changed to integrated diagnosis of A. Histological OA were proven to be A or diffuse midline glioma with H3K27M. There were small number of cases with IDH‐mut which could not be detected immunohistochemically. Although there were cases in which 1p/19q co‐deletion was observed with FISH, some of them showed partial deletion of 1p or/and 19q by MLPA and IDH‐wt by sequencing. There might be some relationship between partial deletion pattern of 1p/19q detected by the MLPA and histological findings.

P3‐34

A case of malignant transformation of NF1‐associated spinal astrocytoma

Sayaka Yuzawa; Yuki Kamikokura; Mishie Tanino; Hidehiro Takei

Department of Diagnostic Pathology, Asahikawa Medical University, Asahikawa, Japan

The most common glioma occurring in patients with neurofibromatosis type 1 (NF1) is a pilocytic astrocytoma, although other types of gliomas such as diffuse astrocytoma and glioblastoma are also known to occur. NF‐1 associated gliomas follow an atypical clinical course and show peculiar histopathologies, and few cases of malignant transformation were described. We present a rare case of malignant transformation of NF1‐associated spinal astrocytoma in a course of 7 years. A 27‐year‐old man with NF1 presented with weakness of lower extremities, and MRI revealed an intramedullary spinal cord tumor involving Th11‐Th12 levels. The tumor was resected and histologically demonstrated a nodular proliferation of atypical spindled cells with relatively thick cytoplasmic processes. Multipolar tumor cells were also seen between these nodules. No necrosis or microvascular proliferation was observed. Immunohistochemically, the tumor cells were positive for GFAP and negative for IDH1 R132H. The MIB‐1 labeling index was approximately 5%. The diagnosis of NF1‐associated astrocytoma, grade II, was rendered. Seven years after the surgery, he developed leg paralysis and was found to have a recurrent tumor, involving the spinal cord from Th5‐L3 levels. Since the spinal cord was completely replaced by tumor below the level of Th8, spinal cordectomy was undertaken. The histopathological examination revealed pleomorphic glial tumor cells infiltrating diffusely into the spinal cord parenchyma, with prominent subarachnoid spreading and nerve root involvement. Both necrosis and microvascular proliferation were observed. The MIB‐1 labeling index was about 20% and the recurrent tumor was diagnosed as a high‐grade infiltrating astrocytoma (malignant transformation).

P3‐35

A case of primary diffuse leptomeningeal gliomatosis with multi‐nodular lesions

Koichi Mitsuya¹; Takuma Oishi²; Ichiro Ito³; Shoichi Deguchi¹; Nakamasa Hayashi¹; Yoko Nakasu⁴

¹Division of Neurosurgery, Shizuoka Cancer Center, Shizuoka, Japan; ²Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan; ³Department of Pathology, Nagano Red Cross Hospital, Nagano, Japan; ⁴Department of Neurosurgery, Shiga University of Medical Science, Otsu, Japan

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal tumor, arises from heterotopic neuroglial tissue in the leptomeninges and spreads widely throughout subarachnoidal space. We report a 72‐year‐old man with PDLG presenting gait disturbance. MRI showed leptomeningeal multi‐nodular mass lesions with gadolinium enhancement. CSF cytology was class 2. Preoperative diagnosis was meningeal carcinomatosis of unknown origin. Open biopsy revealed that the tumor was elastic hard with clear margin. Pathological examination demonstrated composed fascicles of spindle cells with atypical nuclei. Immunohistochemically, the spindle cells were positive for GFAP, oligo2, EMA, S100 and ATRX, but negative for neurofilament. IDH1 was wild type and Ki‐67 labeling index was 30%. Pathological diagnosis was high grade glioma (grade 3). He underwent whole brain radiotherapy and stereotactic radiosurgery boost followed by bevacizumab therapy. He died 5 months after initial presentation. Autopsy was performed, and our diagnosis was PDLG (grade4). We emphasize that PDLG with multi‐nodular lesions must be included in differential diagnosis in cases with MRI suggesting nodular leptomeningeal carcinomatosis of unknown origin, and a biopsy should be performed in the early stages.

P3‐36

A case of diffuse leptomeningeal glioneuronal tumor

Shoh Sasaki^1,2; Tomoya Myoujin²; Kouhei Morita²; Tokiko Nakai²; Ryuta Matsuoka³; Yuto Uchihara⁴; Kazuma Sugie⁵; Takanori Hirose⁶; Chiho Oobayashi²

¹Nara Prefecture General Medical Center, Department of Pathology, Nara, Japan; ²Nara Medical University Hospital, Department of Pathology, Nara, Japan; ³Nara Medical University Hospital, Department of Neurosurgery, Nara, Japan; ⁴Nara Prefecture General Medical Center, Department of Neurology, Nara, Japan; ⁵Nara Medical University Hospital, Department of Neurology, Nara, Japan; ⁶Hyogo Cancer Center, Department of Pathology, Hyogo, Japan

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare tumor, which was recently recognized as a new glioneuronal tumor entity. DLGNT usually occurs in children and young adults and is characterized by prominent and widespread leptomeningeal growth of oligodendroglia‐like tumor cells. Their clinicopathologic features and biological behavior are still unclear. Here, we report an adult case of DLGNT, which showed the aggressive clinical course. The patient was a 42‐year‐old male who visited a hospital, suffering from fever and disturbance of consciousness. Based on signs of meningeal irritation and abnormalities in CNS fluid, meningitis was clinically suspected. Despite antibiotics and steroids treatment, his condition deteriorated, associated with hydrocephalus, paralysis, and incontinence. MRI, which was taken a half year later, demonstrated swelling of spinal cord and diffuse enhancement of leptomeninges throughout the CNS. As neoplastic process was suspected, biopsy was performed from the cauda equina. In the biopsy specimens, there was proliferation of uniform round tumor cells, surrounding spinal nerve fascicles. Tumor cells, arranged in small nests, possessed round nuclei and clear cytoplasm, simulating oligodendroglia. Immunohistochemically, tumor cells were variedly positive for GFAP, Olig2, and synaptophysin. Ki‐67 labeling index was 5‐10%. Based on the pathologic findings, the tumor was diagnosed as DLGNT. Chemo‐radiotherapy was refused and the patient died one month after the diagnosis. Clinical progression of DLGNT is usually slow, but some examples may show the aggressive course. For the appropriate and early diagnosis of this challenging tumor, the acquaintance of DLGNT is mandatory.

P3‐37

Glioblastoma suspected association with Lynch syndrome

Yukitomo Ishi^1,4; Tomoe Kobayashi²; Kazunori Eto²; Tatsuru Noujou¹; Michio Kitagawa³; Motegi Hiroaki⁴; Shigeru Yamaguchi⁴; Hiroyuki Kobayashi⁴; Shinya Tanaka⁵; Utano Tomaru⁶

¹Department of Neurosurgery, Tomakomai City Hospital, Tomakomai, Japan; ²Department of Gastroenterological Medicine, Tomakomai City Hospital, Tomakomai, Japan; ³Tomakomai Eastern Neurosurgery, Tomakomai, Japan; ⁴Department of Neurosurgery, Hokkaido University School of Medicine, Sapporo, Japan; ⁵Department of Cancer Pathology, Hokkaido University School of Medicine, Sapporo, Japan; ⁶Department of Pathology, Hokkaido University School of Medicine, Sapporo, Japan

Background: Lynch syndrome is an autosomal dominant disease caused by aberrations in DNA mismatch‐repairing genes, which present colon cancer and various gastroenterological cancers, urological cancers or brain tumors. Little is known about clinical characteristics of glioblastoma associated with Lynch syndrome.

Case Presentation: The patient is a 50 year‐old male with past history of rectal cancer at the age of 38, and familial history of multiple cancer including renal pelvis cancer, prostate cancer, bladder cancer, colon cancer and skin cancer in his brother. A brain tumor in right parietal lobe was detected due to loss of consciousness, and pathological diagnosis of glioblastoma was provided after surgical resection. Although he underwent local 60Gy of irradiation concomitant with oral administration of temozolomide, additional resection was required due to growth of residual tumor. During maintenance treatment with temozolomide, he underwent several times of polypectomy for a number of colon polyps and ileocecal resection for cecal cancer, which suggested a familial colorectal cancer syndrome. He underwent 24 courses of temozolomide treatment without recurrence. At 40 months after initial operation, he underwent resection surgery for newly detected gadolinium‐enhanced lesion around resection cavity but tumor cells were not confirmed pathologically. However, he eventually experienced recurrence at 47 moths and died at 52 months after initial surgery.

Conclusion: Although genetic examinations have not been performed for present case, Lynch syndrome was strongly suspected by clinical course and familial history. This case suggested the efficacy of standardized treatment with temozolomide.

P3‐38

An operative case of brain stem glioma with IDH1 mutation

Kenichiro Matsuda¹; Kanako Kawanami¹; Kaori Sakurada¹; Rintaro Oe²; Mitsunori Yamakawa²; Yukihiko Sonoda¹

¹Department of Neurosurgery, Yamagata University, Faculty of Medicine, Yamagata, Japan; ²Department of Pathology, Yamagata Universitym Faculty of Medicine, Yamagata, Japan

Introduction: The isocitrate dehydrogenase (IDH) mutation in glioma has been studied with regard to the clinical feature and biological significance. However, the IDH mutation in the brainstem glioma is rare; there are only seven cases in our knowledge. Now, we report the adult brain stem glioma case with IDH mutation who showed secondary malignant change.

Case: 49 years old male. In August 2011, he developed diplopia, and the brainstem tumor was suspected by the image. During the first visit, perceived decrease of sensation in right upper/lower extremities, left abducent palsy, and left facial palsy were recognized. MRI showed T2WI/FLAIR high‐intensity lesion on the left side of pons. Obvious contrast enhancement was not observed. We had underwent biopsy. Pathologically, the tumor showed findings of low‐grade glioma. After surgery, the initial treatment by local irradiation with 54Gy and temozolomide had performed. Then he was carried out temozolomide maintenance therapy in outpatient. However, since January 2017, he developed ataxia and headache. MRI showed the contrast enhanced lesion in the left cerebellar hemisphere. The surgery was performed again. Pathological search showed findings of glioblastoma with IDH mutation. He had died after SRT and conservative treatment in terminal stage.

Consideration: the report on the brainstem glioma with IDH mutation is rare; it is about to be seen in case report and a few cases of multi‐case analysis. This case is also a rare case as an adult brainstem glioma with IDH mutation and malignant transformation. We report the the clinical course with literature examinations.

P3‐39

The anti‐tumor effects of COX‐2 inhibitor against malignant astrocytic tumor cells in vitro and in vivo

Kosuke Katayama; Kenichiro Asano; Hiroki Ohkuma

Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan

Purpose: We examined an anti‐tumor effect of celecoxib (CXB), a COX‐2 inhibitor, combined with temozolomide (TMZ) and irradiation in vitro. CXB exerted an anti‐tumor effects in dose dependent manner, and the viability of C6 cell line was reduced more effectively by CXB when combined with TMZ and irradiation. The present study aimed to define the anti‐tumor effects of CXB alone or combined with TMZ and/or irradiation, against C6 cell line in vivo.

Methods: With the use of C6 cell line, we analyzed the anti‐tumor effect of CXB in vivo. C6 cells (1×10⁵cells) were implanted into mice by stereotactically guided injection into the fore brain. After 7days, mice were treated with CXB (100mg/kg/day IP), TMZ 7.5mg/kg/day IP, irradiation (15Gy), CXB and TMZ, CXB and irradiation, TMZ and irradiation, or CXB and irradiation and TMZ for a week. The tumor volume, invasion and dissemination were analyzed histopathologically.

Result: CXB exerted an anti‐tumor effects more effectively by CXB when combined with TMZ and irradiation in vitro. Here we report the anti‐tumor effect of CXB in vivo.

P3‐40

Stratification of IDH wild‐type WHO grade II / III gliomas by molecular marker

Kiyonori Kuwahara^1,2; Shigeru Ohba¹; Shunsuke Nakae¹; Natsuki Hattori¹; Hikaru Sasaki³; Masato Abe⁴; Mitsuhiro Hasegawa¹; Yuichi Hirose¹

¹Department of Neurosurgery, Fujita Health University; ²Department of Neurosurgery, Fujieda Heisei Memorial Hospital; ³Department of Neurosurgery, Keio University; ⁴Department of Pathology, School of Medical Sciences, Fujita Health University

Background: According to the revision of 2016 WHO Classification of Brain and Central Nervous System Tumors, grade II / III gliomas were classified into astrocytoma and oligodendroglioma with the presence of 1 p / 19 q co‐deletion and IDH mutation. On the other hand, IDH wild‐type grade II / III gliomas are thought to be an of various tumors, but the detail has not been reported. In this report, we indicate the correlation among genetic characteristics about IDH wild‐type grade II / III gliomas and their prognosis.

Methods: Our study included 37 patients of IDH wild‐type grade II / III gliomas. Their first surgery was performed at our hospital from April 2004 to April 2018. We investigated the correlation among Overall Survival (OS) and genetic characteristics, including BRAF V600E, hTERT promoter, p53, ATRX mutation and DNA copy number.

Results: Median OS was 30 months and median PFS was 10 months. DNA copy number at + 7 (p = 0.0004) and ‐ 10 q (p = 0.03) characteristically in glioblastoma, ATRX mutation (p = 0.02) was related with shorter OS significantly. Multivariate analysis for +7, ‐10 q and ATRX mutation, which were a significant factor in univariate analysis, showed that ‐ 10 q significantly contributed to shorter OS.

Conclusions: Our genetic analysis of this study suggested that IDH wild‐type grade II / III gliomas were an aggregate of various tumors, including glioblastoma. We will report additional genetic characteristics of IDH wild‐type grade II / III gliomas.

P3‐41

Three cases of unclassified low‐grade gliomas with presence of numerous CD34‐positive cells

Naomi Oka¹; Masaki Iwasaki²; Shin‐ichoro Osawa³; Masayuki Kanamori³; Kazutaka Jin⁴; Hajime Miyata⁶; Mika Watanabe⁷; Nobukazu Nakazato⁴; Hiroshi Uenohara⁵; Hiroyoshi Suzuki¹

¹Department of Pathology and Laboratory Medicine, NHO Sendai Medical Center; ²Department of Neurosurgery, National Center of Neurology and Psychiatry, Tokyo, Japan; ³Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁴Department of Epileptology, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁵NHO Sendai Medical Center, Department of Neurosurgery; ⁶Department of Neuropathology, Research Institute for Brain and Blood Vessels‐Akita, Akita, Japan; ⁷Department of Pathology, Tohoku University Hospital, Sendai, Japan

We report here three cases of low‐grade gliomas, mainly composed of oligodendroglia‐like cells (OLC) along with numerous CD34‐positive multipolar cells. Two patients were under 10 years old and had chronic epilepsy. Astrocytic tumor cells were also intermingled in the lesion. Dysplastic neurons or glioneuronal elements of DNT were not observed in any of them. Immunostainings revealed OLCs were positive for Olig2 but negative for GFAP or neuronal cell markers. Ki‐67 LIs were less than 3% in all cases. Genetic analysis identified BRAFV600E mutation in two cases. None of them showed IDH1 or 2 mutations. Considering the presence of numerous CD34‐positive cells in the lesion, these tumors might arise based on focal maldevelopmental processes of the brain.

P3‐42

Adult gliomas concurrently harboring 1p/19q codeletion and TP53 mutation: molecular analysis of two cases

Hideyuki Arita^1,2; Toru Umehara¹; Naoki Kagawa¹; Yasunori Fujimoto¹; Eiichi Morii³; Yonehiro Kanemura^2,4; Haruhiko Kishima¹

¹Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan; ²Kansai Molecular Diagnosis Network for Central Nervous System Tumors, Osaka, Japan; ³Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan; ⁴Institute for Clinical Reserach, Osaka National Hospital, Netional Hospital Organization, Osaka, Japan

The diagnosis of “Oligoastrocytoma” is discouraged in the current diagnostic system based on the CNS WHO 2016 because virtually all IDH mutated tumors harbor either 1p/19q codeletion or TP53 mutation, that is a hall mark of oligodendroglioma or astrocytoma, respectively. However, a small portion of 1p/19q codeleted tumors exhibit TP53 mutations. In this study, we reviewed the clinical and genetic features of two cases of “Oligodendroglioma, IDH mutant, 1p/19q codeleted, and TP 53 mutant”. The first case (Case 1) had a history of craniotomy for left frontal tumor 7 years before, and underwent the second surgery for tumor removal in our hospital. The second case (Case 2) underwent repeated surgeries for right frontal tumor recurring locally. Both cases exhibit partial calcification in computed tomographic images. Genetic analysis revealed IDH1 R132H mutation, 1p/19q codeletion, TERT promoter mutation, and missense point mutation in the exon of TP53 in the specimens of the second surgery of the Case 1 and the first and second surgery of Case 2. Loss of heterozygosity (LOH) analysis using microarray technique showed the normal copy number of 17p in all specimens. Our cases lacked copy number neutral LOH of TP53, which are typically observed in IDH‐mutated astrocytomas while having TERT promoter mutations. Although further pathological analysis of intratumoral heterogeneity is needed, our results suggest that low grade gliomas with 1p/19q codeletion and TP53 mutation may have strong features of oligodendrogliomas rather than astrocytomas.

P3‐43

A case of adult supratentorial anaplastic pilocytic Astrocytoma

Naoya Yoshimoto; Yusuke Nakajima; Yoshiki Fujikawa; Hirofumi Tuji; Gen Futamura; Hirokuni Hashikata; Masanori Goto; Namiko Nishida; Jyunya Taki; Koichi Iwasaki

Department of Neurosurgery, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan

Pilocytic Astrocytoma (PA) is most commonly occurs in children, and classified in WHO grade I. However, PA is infrequently seen in adult population and about 1.5% of PA present histologically anaplastic feature. We report a case of adult anaplastic PA (APA).

A 39‐year‐old‐man presented with progressive headache for one week. Clinical examinations revealed no apparent neurological deficit. Brain MRI revealed a mass lesion within the right temporal lobe with a diameter of 28 mm. It demonstrated isointensity on a T1‐weighted image and hyperintensity on a T2‐weighted image with contrast enhancement and severe perifocal edema.

We performed gross total removal of tumor. Tumor was slightly hard and greyish, we used carmustine wafers. Histologically, tumor showed typical biphasic pattern, but with brisk mitotic activity and hypercellularity. There was no necrotic component. As a result of immunohistochemical stains, GFAR, Nestin, Olig2, p53 were positive, IDH1 was negative. MIB1 labeling index was 8.1%. This tumor was diagnosed APA, considering progressive clinical course. We started adjuvant radiotherapy (60Gy) and temozolomide (75mg/m2/day) administration. However, 3 weeks later, MRI revealed enhancement of removal cavity and pial dissemination was suspected. Therefore, we added bevacizumab (10mg/m2/2weeks). Now, follow up MRI after 9 months did not reveal any tumor progression.

We reported a case of adult supratentorial APA. This case was diagnosed as ‘Anaplastic’ PA depending on its progressive course, even though it did not show necrotic component histologically, Overall survival of APA is reported about 2 years. In this case, bevacizumab seems effective, better prognosis can be expected.

P3‐44

Two cases of pilocytic astrocytomas with challenging diagnosis

Makoto Ideguchi¹; Natsumi Fujii¹; Machiko Ohno¹; Taichi Shimabukuro¹; Norio Ikeda¹; Takafumi Nishizaki¹; Eiji Ikeda²

¹The Department of Neurosurgery, Ube‐Kohsan Central Hospital, Ube, Japan; ²The Department of Pathology, Yamaguchi University Graduate School of Medicine

Pilocytic astrocytoma (PA) is tumor in young people, the common locations of which were cerebellum, the optic pathway and the fourth ventricle. We report the cases with challenging diagnosis due to their atypical location, imaging and pathology.

Case 1: A 7‐year‐old boy with right hemiparesis onset. The imaging showed the enhanced multi‐cystic tumor with calcification located in left basal ganglia. Craniotomy was used to perform the tumor resection. Pathological findings: Astrocyte‐like tumor cells increased in myxoid change‐background with microcalcification. While mitosis and microvascular proliferation were not seen, the invasive feature was observed. Immunohistochemical staining (IHC) was positive for GFAP, Olig2, ATRX, and p53, but negative for IDH1‐R132H and BRAF‐V600E. MIB1‐LI was 10%. Although one of the preoperative diagnoses was diffuse midline glioma, the final diagnosis was PA from the results of H3K27 wild type and of BRAF‐V600E mutation by direct sequence.

Case 2: A 25‐year‐old woman with epilepsy onset. The imaging showed non‐enhanced tumor located in right lateral ventricle. Endoscopic biopsy was performed. Pathological findings: Astrocyte‐like tumor cells increased in compact and spongy background. Microvascular proliferation and eosinophilic granular bodies were seen. IHC showed positive for GFAP, Olig2, ATRX, and p53, but negative for IDH1‐R132H and BRAF‐V600E. MIB1‐LI was 2%. While preoperative diagnosis was subependymoma, the final one was PA.

Although most PA cases can be diagnosed from imaging findings alone, atypical locations and a non‐enhancing feature sometimes make accurate diagnosis difficult. Moreover, since there are cases with high MIB1‐LI and invasive features, we suggest the indispensability of comprehensive diagnosis.

P3‐45

Three case reports of radiation‐induced glioblastoma after complete remission of acute lymphoblastic leukemia

Masayuki Kanamori¹; Ryuta Saito¹; Takumi Kajitani¹; Mika Watanabe²; Hirosyoshi Suzuki³; Yuko Watanabe⁴; Shigeo Kure⁴; Teiji Tominaga¹

¹Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan; ²Department of Pathology, Tohoku University Hospital, Sendai, Japan; ³Department of Pathology and Laboratory Medicine, National Hospital Organization Sendai Medical Center, Sendai, Japan; ⁴Depatrment of Pediatrics, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, Japan.

Radiation therapy is sometimes performed to control intracranial acute lymphoblastic leukemia (ALL), but may lead to radiation‐induced malignant glioma. The clinical, radiological, histological, and molecular findings are described of three cases of radiation‐induced glioblastoma after treatment for ALL. They received radiation therapy at age 6‐ 8 years. The latency from radiation therapy to the onset of radiation‐induced glioblastoma was 5‐ 10 years. Magnetic resonance imaging demonstrated diffuse lesions with multiple nodular small enhanced lesions in all cases. Histological examination showed that the tumors consisted of mainly small round astrocytic atypical cells in one case, and astrocytic atypical cells with elongated cytoplasm and nuclear pleomorphism with small cell component in two cases. Microvascular proliferation was present in all cases. Immunohistochemical analysis for isocitrate dehydrogenase 1 R132H and B‐Raf V600E, and mutational analysis for the isocitrate dehydrogenase (IDH) 1, IDH2, and H3F3A gene revealed the wild‐type alleles in all three cases. The integrated diagnoses were isocitrate dehydrogenaseIDH wild‐type glioblastoma, and local irradiation and concomitant temozolomide were performed. After initial treatment, significant shrinkage of the diffuse lesion and enhanced lesion was found in all cases. Radiation‐induced glioblastoma occurring after treatment for ALL had unique clinical, radiological, histological, and molecular characteristics in our 3 cases.

P3‐46

A cerebellopontine angle tumor mimicking an extra‐axial mass

Mitsuru Tamura¹; Fumitaka Matsumoto¹; Munetomo Futami¹; Kiyotaka Yokogami¹; Tsuyoshi Fukushima²; Hideo Takeshima¹

¹Department of Neurosurgery, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki; ²Department of Oncopathology and Regenerative Biology, Division of Pathology, Faculty of Medicine, University of Miyazaki

A 70 years old woman suffering right hearing disturbance for 5 years and dizziness for 8 months. Head magnetic resonance imaging (MRI) revealed a large cerebellopontine angle (CPA) tumor. Because this tumor was well demarcated and was thought as an extra‐axial mass. This tumor was hypo‐intensity on T1‐weighted image, hyper‐intensity on T2 weighted image, and was homogeneously enhanced by Gd‐DTPA. This tumor seemed to relate with root exit zone of right trigeminal nerve, thus, we preoperatively diagnosed root type trigeminal schwannoma. We performed tumor resection by right retro‐sigmoid approach. Operative view revealed that this tumor did not have a relationship with the trigeminal nerve, but tightly attached to the ventrolateral portion of pons. This tumor was arose from pons and exophytically grew toward CPA. Histological diagnosis was glioma.

P3‐47

A case of extraventricular subependymal giant cell astrocytoma in an infant

Nobushige Tsuboi¹; Kazuhiko Kurozumi¹; Tatsuya Sasaki¹; Hiroyuki Yanai²; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; ²Department of Pathology, Okayama University Hospital, Okayama, Japan

Introduction: Subependymal giant cell astrocytoma (SEGA) and subependymal nodules (SEN) are the most common central nervous system tumors in patients with tuberous sclerosis complex (TSC). We report a case of extraventricular SEGA in an infant.

Case Report: A 2‐month‐old infant had bilateral eyelid‐ and tongue spasms after feeding. Computed tomography (CT) scan revealed multiple lesions in the right frontal lobe and bilateral basal ganglia. Magnetic resonance imaging (MRI) of those lesions showed hyperintense T1‐weighted images, and hypointense T2‐weighted images. He was diagnosed with TSC because he had white, leaf‐shaped macules. Electroencephalographic examination showed the epileptic focus to be located in the right frontal lobe, for which he underwent a lesionectomy of the frontal area. After surgery, the seizure was well controlled. The specimen showed gangliocyte‐ and gemistocyte‐like giant cells with eosinophilic cytoplasm, and neurocytes with Nissl granules. The pathologic diagnosis was SEGA.

Discussion: SEGA is often located near the foramen of Monro, and develops from the lateral ventricular walls. Most patients with SEGA present with symptoms of hydrocephalus. Extraventricular SEGA is rare compared with intraventricular SEGA.

Conclusion: We present here a case of extraventricular SEGA in an infant, who should be carefully followed up because he may require additional treatment such as secondary surgery or molecular‐targeted therapy.

P3‐48

A case of astroblastoma

Yu Kawanishi¹; Shinya Higuchi⁴; Yuichiro Kondo⁴; Eiichi Nakai²; Hitoshi Fukuda²; Naoki Fukui²; Takahito Nakajou²; Makoto Hiroi³; Tetsuya Ueba²

¹Department of Neurosurgery, Aki General Hospital, Kochi, Japan; ²Department of Neurosurgery, Kochi Medical School; ³Laboratory of Diagnostic Pathology, Kochi Medical School Hospital; ⁴Department of Neurosurgery, Chikamori Hospital

Introduction: Astroblastoma is a rare, mostly supratentorial glial tumor, occurring predominantly in children and young adults. Due to the rarity, treatment strategies are still to be discussed.

Case: A six year old male presented with headache and nausea. MRI revealed a left frontal cystic mass lesion with bubbly contrast enhancement and macrocalcifications. After gross total tumor resection histological examination showed the tumor contained neoplastic cells with astroblastic arrangements. A striking perivascular array of pseudorosettes was also found. In the end, the diagnosis of high grade astroblastoma was rendered. Eighteen months later, the patient was suggested a local recurrence and received stereotactic radiotherapy. The last MRI follow‐up 12 months after irradiation showed no further recurrence. Classification and histogenesis of this tumor is still debated. Lack of clinicopathological correlation makes the prognosis of this tumor unpredictable.

P3‐49

A case of anaplastic astroblastoma in the elderly

Naohisa Miyagi¹; Sousyou Kajiwara¹; Hideo Nakamura¹; Satoru Komaki²; Takuya Furuta²; Yasuo Sugita²; Motohiro Morioka¹

¹Department of Neurosurgery, Kurume University School of Medicine, Kurume, Japan; ²Department of Pathology, Kurume University School of Medicine, Kurume, Japan

Although astroblastoma is a rare variant of gliomas, the anaplastic type and/or the elderly case were especially rare. We report a case of anaplastic astroblastoma in the elderly. A 72‐year‐old female presented with progressive dementia was admitted to our hospital. Brain MRIs showed multinodular and multicystic masses with ring‐like enhancement in the right temporal lobe. Partial resection was performed and pathological examination showed a high‐grade glioma. Postoperatively, she was treated with a combination of radiation therapy and temozolomide chemotherapy. However, gradually progressive consciousness disturbance appeared during postopertive treatment, MRIs revealed the rapid and massive regrowth of the residual tumor. Therfore re‐subtotal resection was additionally performed. In the histopathological examination of the first and second surgical specimens, highly proliferation of round eosinophilic tumor cells with mitotic figure and pleomorphism were observed. Astroblastic pseudorosette and perivascular hyalinazation were confirmed. In immunohistochemical staining, the tumor cells were positive for GFAP, ATRX and BRAF V600E, negative for EMA, CAM5.2, IDH1 and H3K 27M. The staining index of MIB‐1 was 20%.

P3‐50

Sellar ependymoma with sinus invasion: the ninth case report and review of literature

Mihai Gheorghe Lisievici¹; Diana Pasov¹; Laurentiu Catalin Cocosila¹; Vasile Ciubotaru²; Ligia Tataranu²

¹Bagdasar‐Arseni Clinical Emergency Hospital, Department of Pathology; ²Bagdasar‐Arseni Clinical Emergency Hospital, Department of Neurosurgery SNC III

Introduction: Ependymoma is a common type of glioma which can rarely develop outside of the ventricular system. Within the pituitary region however only eight cases have been encountered to date.

We report the ninth.

Methods: Our patient, a 64 years old female was referred for neurosurgical evaluation after complaining of visual disturbance and headaches, accompanied by signs of panhypopituitarism. Neuroimaging revealed a large sellar mass extending to the cavernous as well as sphenoid sinuses which was interpreted as a nonfunctional pituitary macroadenoma. Transsphenoidal resection was decided and both sinusal and sellar components were removed.

Results: Histopathological evaluation of classical hematoxilin‐eosin slides revealed the typical features of an ependymoma. Due to the presence of a high mitotic index and large areas of necrosis in the sellar component, our case was ultimately considered anaplastic though prognostic significance is debatable here. Imunohistochemically, the tumor showed strong, diffuse positivity for GFAP and S100 as well as a Ki67 index of 28%.

Conclusion: The first sellar ependymoma was reported in 1956 and only seven others have been described afterwards. The origin of this neoplasm has been theorized as either from a small population of “ependymal pituicytes” or a defect of migration during embriogenesis. All reported cases presented typical histology and only two were subjected to long term follow up. While data about the older cases is limited, it appears our case is the first showing anaplastic features as well as extension to the sinusal mucosa. Further clinical significance is to be established as this unusual case is being followed up.

P3‐51

Anaplastic ependymoma with ganglioneuronal differentiation

Soichiro Fushimi¹; Machiko Hotta¹; Masanori Shiohara¹; Takanori Hirose²; Yoji Wani¹

¹Department of Pathology, Himeji Red Cross Hospital; ²Department of Pathology, Hyogo Cancer Center

6‐year‐old Japanese boy without previous medical problem presented with recurrent vomiting and gradually deteriorated headache for 3 weeks. Computed tomography and magnetic resonance imaging of the brain revealed a multicystic heterogenous ring enhancing mass in left occipital lobe. He underwent drainage for intracranial pressure control and the lesion was biopsied. Microscopically, the tumor was composed of areas with small round cells and areas with large polygonal cells. In the former area, tumor cells formed perivascular rosettes and true rosettes. Necrosis and microvascular proliferation and mitoses were noted. Immunohistochemically, L1CAM was diffusely positive. Thus the tumor was diagnosed as ependymoma, RELA‐fusion positive. In the latter area the polygonal cells, which are with round nuclei and prominent nucleoli and abundant eosinophilic cytoplasm, reminiscent to ganglion cells. Mitoses were also noted. Immunohistochemical study of GFAP, neurofilament and synaptophysin and NeuN clarified neuronal differentiation in addition to glial differentiation. Finally the tumor was diagnosed as anaplastic ependymoma with ganglioneuronal differentiation.

P3‐52

Upregulation of Programmed Cell Death Ligand 1 (PDL1) expression in RELA fusion positive ependymomas suggests a role for immunotherapy in these aggressive tumors

Mehar Chand Sharma¹; Agrima Sharma¹; Prit Benny Malgulwar¹; Manmohan Singh²; Vaishali Suri¹; Chitra Sarkar¹

¹Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, India; ²Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Introduction: RELA‐fusion positive supratentorial (ST‐RELA) ependymomas are an aggressive subset associated with poor prognosis. The oncogenic C11orf95‐RELA fusions result in constitutive NF‐kB pathway activation, with the latter known to play important roles in inflammation and innate immunity. Recent advances in cancer immunotherapy has seen the development of treatments targeting immune check point interactions such as Programmed Cell Death Ligand 1 (PDL1/CD274) and its receptor, Programmed Death‐1 (PD‐1). PDL1/PD‐1 inhibitors are now in clinical use for advanced lung and urothelial carcinomas expressing PDL1, while clinical trials are ongoing in several brain tumors. We analyzed the expression of PDL1 in ST‐RELA ependymomas to study the applicability of anti‐PDL1 immunotherapy in this aggressive subset.

Methods: Quantitative‐Real time PCR for Type I and II C11orf95‐RELA fusions was performed followed by Sanger sequencing. Gene expression analysis was performed for PDL1. ChIP‐qPCR was performed to study the interaction of RelA protein with PDL1 gene.

Results: 41 supratentorial ependymomas were included, of which 25 cases harboured RELA fusions (60%). ST‐RELA ependymomas predominated in children (80%) and were frequently of Grade III histology (76%). PDL1 was significantly overexpressed in ST‐RELA ependymomas. ChIP‐qPCR demonstrated enrichment of RelA on PDL1 promoter.

Conclusion: The present study reports significant over‐expression of PDL1 in supratentorial ependymomas harbouring RELA fusions and demonstrates a physical cross‐talk between RelA and PDL1 gene. In addition to suggesting a role for anti‐PDL1/PD1 immunotherapy, this study raises the need to delve into the immune microenvironment and various immune networking signals to better understand the pathogenesis of RELA fusions.

P3‐53

Improved risk‐stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features

Stephanie Juenger¹; Martin Mynarek³; Evelyn Doerner¹; Anja zur Muehlen¹; Katja von Hoff³; Stefan Rutkowski³; Andre von Bueren³; Felipe Andreiuolo¹; Torsten Pietsch^1,2

¹Institute of Neuropathology, Univerity of Bonn, Germany; ²DGNN Brain Tumor Reference Center, Germany; ³Department of Pediatric Hematology/Oncology, Univerity Clinics Hamburg‐Eppendorf, Hamburg‐Germany

Introduction: Currently, treatment protocols for children with posterior fossa ependymomas are risk‐adapted by clinical features (age, extent of resection). We aimed to identify independent histological and molecular outcome predictors to develop improved stratification models.

Methods: Tumor samples of 134 patients (0.2 ‐ 15.9 years) enrolled between 1999 and 2010 and treated according to the risk‐adapted German GPOH‐HIT protocols were analyzed for histological and immunohistological features including mitotic activity, necrosis, vascular proliferation and H3‐K27me3 expression as well as genomic alterations by SNP and methylation array hybridization and molecular inversion probe analysis (MIP). Survival analysis was performed by Kaplan‐Meier method with log rank test and Cox regression.

Results: The majority of the samples were anaplastic corresponding to WHO grade III tumors and PFA posterior fossa ependymomas; 7 PFB tumors were identified (5.2%). Residual tumor, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event‐free (EFS) and overall survival (OS). Furthermore, vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. PFB assignment was not significantly associated to outcome. Multivariate Cox regression revealed residual tumor, chromosome 1q gain, vascular proliferation and high mitotic activity as independent predictors of OS; for EFS, chromosome 1q gain, residual tumor and mitotic activity were predictive. The independent predictors for outcome were used to develop an improved 3‐tiered risk‐stratification model.

Conclusion: The independent outcome predictors residual tumor, chromosome 1q gain and mitotic activity could be integrated in an improved risk‐stratification model for posterior fossa ependymoma of childhood that outperforms current stratification procedures.

P3‐54

CNS high‐grade neuroepithelial tumor with BCOR internal tandem duplication: a histopathological and molecular genetic analyses of six cases

Yuka Yoshida¹; Sumihito Nobusawa¹; Satoshi Nakata^1,2; Tatsuya Yamazaki¹; Junko Hirato³; Hideaki Yokoo¹

¹Department of Human Pathology, Gunma University Graduate School of Medicine; ²Department of Neurosurgery, Gunma University Graduate School of Medicine; ³Department of Pathology, Gunma University Hospital

Introduction: Central nervous system high‐grade neuroepithelial tumors with BCOR alteration (CNS HGNET‐BCOR) are a recently reported rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so‐called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3’ end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD‐positive tumors have been reported to share similar pathological features.

Methods: We performed a clinicopathological and molecular analysis of six cases of CNS HGNET‐BCOR, and compared them with their counterparts in the kidney and soft tissue.

Results: Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET‐BCOR exhibited glial cell morphology, ependymoma‐like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S‐100 protein and synaptophysin were observed in CNS HGNET‐BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI.

Conclusion: Although CNS HGNET‐BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD‐positive tumors, only CNS HGNET‐BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET‐BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.

P3‐55

Integrated histo‐radio and molecular study of high‐grade gliomas in teenagers

Alexandre Roux^1,2,3; Johan Pallud^1,2,3; Raphael Saffroy⁴; Myriam Edjlali⁵; Marie‐Anne Debily⁶; Nathalie Boddaert⁷; Stephanie Puget⁷; Karima Mokhtari⁸; Dominique Figarella‐Branger⁹; Pascale Varlet¹⁰

¹Department of Neurosurgery, Sainte‐Anne Hospital, Paris, France; ²Paris Descartes University, Paris, France; ³IMA‐Brain, Inserm U894, Institute of Psychiatry and Neuroscience of Paris, Paris, France; ⁴Department of Biochemistry, Paul‐Brousse Hospital, Villejuif, France; ⁵Department of Neuroradiology, Sainte‐Anne Hospital, Paris, France; ⁶UMR8203 Vectorologie et Therapeutiques Anticancereuses Centre National de la Recherche Scientifique, Gustave Roussy, Univ. Paris‐Sud, Universite Paris‐Saclay, Villejuif, France; ⁷Department of Neurosurgery, Necker Enfants‐Malades Hospital, Paris, France; ⁸Department of Neuropathology, Pitie‐Salpetriere Hospital, Paris, France; ⁹Department of Pathology and Neuropathology, La Timone Hospital, AP‐HM, Marseille, France; ¹⁰Department of Neuropathology, Sainte‐Anne Hospital, Paris, France

Introduction: We performed a multicentric retrospective study of teenager patients from both adult and pediatric Ile‐de‐France neurosurgical units, between 1998 and 2013 with a histologically proven high‐grade glioma (HGG) to determine their histo‐radio‐molecular profile.

Methods: We included 85 teenager patients with a grade III or IV glioma according to the following inclusion criteria: age at diagnosis between 15 and 25 year‐old, pathological diagnosis of HGG, available clinical data, pre‐surgical and follow‐up MRI. All MRI and tumoral samples have been centrally reviewed, while blind to initial diagnosis and follow‐up data. We performed a direct sequencing for Histone, IDH and BRAF mutations. A consensus and integrated neuropathological diagnosis was reached by 3 neuropathologists, according to the 2016 World Health Organization classification of tumors of the Central Nervous System.

Findings: The most frequent histomolecular subtype is a pediatric‐like HGG profile with Histone H3 mutation (33/85: 38.8%): 22 H3K27M‐mutants (25.9%) and 11 H3G34R‐mutants (12.9%). Compared to the exclusively pediatric HGG series, the percentage of IDH‐mutant gliomas appears to be more important, reaching 29.4% with only 2 IDH‐mutant 1p19q co‐deleted oligodendrogliomas. Concerning the rarest mutations, we found 2 (2.4%) Mismatch repair cancer syndrome (MMR), 1 BRAF‐mutant (1.2%), and 1 NF1‐mutant (1.2%). The histone and IDH wildtype tumors (27%) will benefit from whole exome or RNA sequencings.

Conclusion: HGG in teenagers comprise a clinicopathological and biological heterogeneous groups of tumours, with a high proportion of pediatric‐subtypes: Histone mutated or MMR. Whole exome sequencing will eventually help refining the Histone or IDH wild type tumors to emerging subgroups

P3‐56

H3K9 methyltransferase inhibitor BIX01294 inhibits tumorigenicity in diffuse intrinsic pontine glioma and glioblastoma

Hiroaki Miyahara^1,2; Manabu Natsumeda^2,3; Michael Koldobsky²; Yang Liu²; Harpreet Kaur²; Laura Asnaghi²; Mari Yoshida¹; Charles G Eberhart²; Eric H Raabe²

¹Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University; ²Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD. USA; ³Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Introduction: Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment‐refractory pediatric brain tumor. It is well known that 70‐80% of DIPG has mutation of H3K27, which acts as one of the major chromatin repressors. Recent studies revealed the H3K27 mutation caused inactivation of H3K27me3 and activation of several oncogenes, but the role of other chromatin repressor including H3K9 methylation in DIPG is still unclear.

Methods: We used 3 DIPG lines with H3K27 mutation (JHH‐DIPG1, SF7761 and SU‐DIPG‐XIII) and 2 glioblastoma (GBM) lines without H3K27 mutation (JHH520 and HSR‐GBM1), and asessed the therapeutic effects of BIX01294 in these cell lines.

Results: DIPG lines showed high expression of H3K9me2 and H3K9me3 compared to GBM lines. Micromolar levels of H3K9 methyltransferase inhibitor BIX01294 suppressed the growth of all cell lines. And 2 µM BIX01294 reduced expression of H3K9me2 in all cell lines, but H3K9me3 in only JHH‐DIPG1, SF7761 and HSR‐GBM1. Proliferation capacity was suppressed after treatment with 2 µM BIX01294 in DIPG lines but not in GBM lines. Moreover, 2 µM BIX01294 induced apoptosis and enhanced radiotoxicity in JHH‐DIPG1, SF7761 and HSR‐GBM1. Clonogenicity was markedly suppressed after treatment with 1 µM BIX01294 in SU‐DIPG‐XIII, JHH520 and HSR‐GBM1.

Conclusion: We conclude that H3K9 methyltransferase inhibition is a promising potential candidate for DIPG and GBM treatment.

P3‐57

Molecular neuropathological classification of pediatric diffuse gliomas WHO‐grade II ‐Annotation to biologically different disease entities

Torsten Pietsch^1,2; Marco Gessi¹; Daniela Kandels³; Monica Warmuth‐Metz⁴; Brigitte Bison⁴; Rene Schmidt⁵; Rolf‐Dieter Kortmann⁶; Astrid Gnekow³

¹Institute of Neuropathology, University of Bonn, Germany; ²DGNN Brain Tumor Reference Center, Germany; ³Swabian Children's Cancer Center, Children's Hospital, Klinikum Augsburg, Germany; ⁴Institute of Neuroradiology, University of Wuerzburg, Germany; ⁵Institute of Biostatistics and Clinical Research, University of Muenster, Germany; ⁶Department of Radio‐Oncology, University of Leipzig, Germany

Objective: We investigated the frequency of distinct histologically and molecularly defined tumor entities in pediatric diffuse gliomas WHO grade II (DG2) and their outcome.

Patients & Methods: 100 DG2 among 1645 pediatric low‐grade gliomas of the SIOP‐LGG‐2004 cohort were identified by central neuropathological review (median age, 9.44 years (0.8‐17.8); NF1 4%). Localization cerebral hemispheres 42, supratentorial midline 27, focal pontine‐medullary 11, cerebellar 10, spinal 10 cases. FFPE material was available from 64 DG2 for molecular evaluation combining immunohistochemistry, pyrosequencing, DNA methylation array and RNA‐fusion analysis including BRAF fusions (Nanostring).

Results: In these 64 cases, we identified 10 IDH‐, 4 Histone3‐K27M‐, 12 BRAF‐V600E‐mutated DG2, 6 with KIAA1549‐BRAF‐fusion, and 32 DG2 wild‐type for IDH/H3/BRAF. Further rare aberrations were revealed by Nanostring RNA‐analysis and methylation profiling. All H3‐mutated DG2 were located in the midline und all IDH‐mutated DG2 in the cerebral hemispheres. Treatment included surgical resections without (n=68/100) or with subsequent non‐surgical therapy (chemotherapy, irradiation, or multiple salvage treatments). 5‐year‐OS in the whole DG2 cohort (n=100) was 89.6% (±3.1%). 13 patients died with tumors located in the thalamus (6), caudal brain‐stem (4) or elsewhere (3). Molecular classification showed, that 4/4 patients with Histone3‐K27M‐, 1/10 IDH‐, 1/12 BRAFV600E‐mutated, 0/6 BRAF fusion positive, 3/32 IDH/H3/BRAF wild‐type tumors died.

Conclusions: Pediatric DG2 represents a heterogeneous group of genetically defined, biologically different tumors. Histone3‐K27M‐mutation was associated with tumor progression and death, while other genetic features lacked prognostic impact. Therefore, even in histologically low‐grade diffuse gliomas a histone3‐K27M mutated midline glioma should be ruled out.

P3‐58

Giant cell glioblastoma in a 7‐year‐old Japanese girl: a case report

Hirohito Yano¹; Noriyuki Nakayama¹; Saori Endo²; Shiho Yasue²; Michio Ozeki²; Natsuko Suzui³; Kazuhiro Kobayashi³; Tatsuhiko Miyazaki³; Toshiyuki Fukao²; Toru Iwama¹

¹Department of Neurosurgery, Gifu University Graduate School of Medicine, Japan; ²Department of Pediatrics, Gifu University Graduate School of Medicine, Japan; ³Pathology Division, Gifu University Hospital, Japan

Introduction: Giant cell glioblastoma (GCG) is a rare variant of glioblastoma multiforme (GBM). Although it occurs at a younger age than ordinary GBM, its occurrence in childhood is very rare.

Clinical summary: A 7‐year‐old Japanese girl presented with headache and restlessness. Magnetic resonance imaging revealed a massive tumor 7 centimeters in diameter in her left frontal lobe with dissemination into the basal cistern. The tumor extended to the lateral ventricles causing acute hydrocephalus due to obstruction of the foramen of Monro. At first, she underwent ventricular drainage and neuro‐endoscopic biopsy from the posterior horn of the left lateral ventricles. The initial pathological diagnosis indicated an atypical teratoid/rhabdoid tumor. After the dissemination subsided due to the first chemotherapy including dacarbazine, carboplatin, and vincristine, she underwent the first tumor resection via a left frontal transcortical approach. Then she received a second chemotherapy including ifosfamide, cisplatin, and etoposide; however, the residual tumor showed no change. A near total resection was achieved by a second, transcallosal approach, leading to improvement of the hydrocephalus. Receiving again chemotherapy, her symptoms improve now.

Pathological findings: Hematoxylin‐eosin (HE) staining of the resected tumor revealed diffuse proliferation of large‐sized pleomorphic cells with abundant cytoplasm and multiple bizarre nuclei, which were sometimes eccentrically located. Additionally, numerous mitoses and pseudopalisading surrounding necrotic foci were found. Immunohistochemistry disclosed a diffuse positivity for SMARCB1 (INI‐1) and a limited positivity for glial fibrillary acidic protein resulting in the final diagnosis of GCG.

Conclusion: Pediatric GCG presenting dissemination at initial diagnosis is rare.

P3‐59

A novel case of recurrent intraventricular atypical central neurocytoma with prominent gangliogliomatous differentiation in a 10 year‐old boy with 10 years of follow‐up

Char Loo Tan¹; Daniel Landi²; Herbert Fuchs²; Roger E McLendon²

¹Department of Pathology, National University Hospital System; ²Duke University Medical Center

Introduction: Central neurocytoma (CN) is a rare neuronal tumor that typically occurs in young adults. Infrequently, these tumors exhibit advanced neuronal maturation and glial differentiation, giving rise to a histologically diverse tumor, in contrast to a typical CN.

Clinical summary: The patient was a 10 year‐old boy who presented with gait changes, headache and vomiting. MRI brain showed a large, 5cm, irregular, partially cystic enhancing lesion centered in the left lateral ventricle and extending into the basal ganglia and thalamus. He underwent subtotal resection. His disease was stable for roughly 4 years, then demonstrated slow, steady growth and he developed right sided weakness. MRI brain performed 10 years after the first resection again showed massive recurrence in the left lateral ventricle. He underwent a second subtotal resection. Adjuvant therapy was recommended after the second resection.

Pathological findings: Both resection specimens showed a dimorphic population of tumor cells. One population exhibited hypercellular sheets of uniform neurocytic cells, constituting the CN component; the second population showed large, dysplastic ganglionic cells in fibrillary background, constituting the area with gangliogliomatous differentiation. Atypical features, including microvascular proliferation and elevated mitotic activity were identified in the recurrent specimen.

Conclusion: Our case demonstrated a rare CN in a pediatric patient with prominent gangliogliomatous differentiation that developed atypical features in the recurrent specimen. This case may provide insight into the divergent differentiation capability of a neurocytic tumor and illustrates diverse histological features of this rare entity.

P3‐60

Central neurocytoma of the third ventricle in Indian subcontinent ‐ a rare case report

Madhu Kumar; Suresh Babu; Shikha Khati; B K Ojha

Pathology departmentKing George's Medical University

Introduction: Central neurocytomas are slow‐growing primary brain tumors of neuronal origin, grows from foramen of Monro or septum pellucidum into lateral or third ventricle. Most common neoplasm in young adults but still < 1% of all CNS tumors. We present this case in 13 years old male because of its rarity, especially in this age and its location.

Clinical summary: A 13year old male boy presented with headache, nausea and vomiting for 1month duration. On & off seizures and weakness in both lower limbs are also present for the past 15 days. On magnetic resonance imaging of the brain shows heterogeneous enhancing lesion in intraventricular area of left choroid plexus. Intraoperatively, tumor was soft, sucable, greyish white with ill defined margins. Clinical and MRI finding was left choroid plexus carcinoma. CT scan findings are suggestive of central neurocytoma. The patient was operated, and craniotomy was done. Tumor tissue sent for histopathology for the confirmation of diagnosis.

Pathological findings: Tumor tissue received as multiple gray brown to greyish white, soft tissue pieces collectively measuring 2x2cm in size. Whole embedded, sections cut, stains with hematoxylin &eosin. On histopathology, monomorphic, small sheets of atypical cells, round to oval to hyperchromatic nuclei with occasional nucleoli and mitotic activity was noted. On immunohistochemistry, GFAP & EMA were negative, both synaptophysin and NSE were positive helping us to arrive at the diagnosis of central neurocytoma.

Conclusion: The immunohistochemical stains make the diagnosis central neurocytoma much easier and rule‐out other differential diagnoses such as choroid plexus carcinoma.

P3‐61

Disseminated atypical extraventricular neurocytoma without mitosis or necrosis

Yasushi Shibata¹; Ryota Mashiko¹; Norio Takayashiki²; Noriaki Sakamoto³

¹Department of Neurosurgery, Mito Medical Center, University of Tsukuba; ²Department of Pathology, Mito Medical Center, University of Tsukuba; ³Department of Pathology, University of Tsukuba

Introduction: Extraventricular neurocytoma is a rare tumor and only a small number of case series have been reported. The WHO brain tumor classifications include extraventricular and central neurocytoma as neuronal and mixed neuronal‐glial tumors.

Clinical summary: The patient was a 57‐year‐old man who visited a general hospital complaining of headache of 3 months in duration. MRI demonstrated multiple spreading lesions. Over a two‐month period, the patient was examined for various infectious diseases at the outpatient clinic of the department of infectious diseases. However, no abnormalities were detected. MRI performed at this time showed the progression of the tumor. MRI showed extra‐axial and intra‐axial tumor with right temporal cyst and seeding. All tumors showed heterogeneous contrast enhancement. Partial right temporal tumor removal was performed for a histological examination. The extra‐axial tumor margin was clear, while the intraaxial tumor margin was not clear.

Pathological findings: The tumor had an enlarged round nucleus, granulated chromatin, and clear cytoplasm. Atypical tumor cells grew in dense honeycomb‐like pattern. No necrosis or mitosis was observed. Immunostaining revealed the following findings: PAS(‐), S‐100(+), synaptophysin(+), Olig2(+), GFAP(‐), pancytokeratin(‐), EMA(‐), CD10(‐), HMB45(‐), c‐kit(‐), PLAP(‐), hCGbeta(‐), CD3(‐), CD20(‐), CD30(‐), IDH1(‐), ATRX(+), NeuN(‐); the MIB‐1 labelling index was 13.9%. We diagnosed the tumor as extraventricular neurocytoma.

Conclusion: The preoperative clinical and radiological findings and the atypical tumor cells and high MIB‐1 index were malignant findings. However, neither mitosis nor necrosis was found, and tumor shrinkage was observed after surgery.

P3‐62

Molecular and histologic characterization of 40 cases of dysembryoplastic neuroepithelial tumors: a multi‐institutional study from the United States of America and Italy

Lea F Surrey¹; Zhao Xiaonan¹; Palay Jain²; Philip B Storm³; Brian Harding¹; Angela J Waanders²; Marilyn M Li¹; Anna Maria Buccoliero⁴; Mariarita Santi¹

¹Department of Pathology and Laboratory Medicine, Childrens Hospital of Philadelphia, PA, USA; ²Center for Data Driven Discovery in Biomedicine, Childrens Hospital of Philadelphia, PA, USA; ³Department of Surgery, Division of Neurosurgery, Childrens Hospital of Philadelphia, PA, USA; ⁴Department of Pathology, Meyer Children Hospital, Florence, Italy

Introduction: Dysembryoplastic neuroepithelial tumors (DNT) are identified by their hallmark specific glioneuronal elements with mucin‐matrix floating neurons; however, a proportion preclude confident classification. We explored histology and molecular alterations of DNTs to identify signature profiles.

Methods: A retrospective review of 40 patients with DNT and low grade glial‐neuronal tumors (GNT) from the Childrens Hospital of Philadelphia (n=33) and Meyer Childrens Hospital of Florence (n=7) was performed (classic ganglioglioma excluded). Tumor histology was examined and genomic data was collected. Genomic methodology included fusions by anchored multiplex PCR, BRAF by Sanger sequencing, 237 cancer gene panel by next generation sequencing (NGS), and copy number variants (CNVs) by genome wide array or NGS.

Results: The average age was 10 years with 2:1 M:F. Two‐thirds represented primary tumors. Some genomic data was available for 33 tumors. DNT morphology represented 80% (23/32 with specific glial‐neuronal component) with generic features of GNT in 20%. Fusions with FGFR2, NTRK2, and BRAF were identified in 5/19 and were mutually exclusive with BRAF V600E (5/29). Additional mutations were identified in FGFR1 (n=2), KDM5C, and PDGFRA. 9/28 contained CNVs. Germline cancer predisposition syndromes were identified in 17% (ATM twice, NF1).

Conclusion: Our data show various genetic alterations affecting the MAPK signaling pathway in DNTs, including a 26% rate of gene fusions. Additionally, we identified a potential association with ataxia‐telangiectasia. Given the spectrum of genetic abnormalities and small size a definitive genetic profile distinguishing classic DNT was not identified.

P3‐63

Epigenetic, genomic, histopathological and imaging integrative work on pediatric dysembryoplastic neuroepithelial tumors

Melanie Pages^1,2,3; David TW Jones⁴; Marie‐Anne Debily⁵; Arnault Tauziede‐Espariat¹; Nathalie Boddaert⁶; Thomas Blauwblomme⁷; Dominique Figarella‐Branger⁸; Rameen Beroukhim³; Pascale Varlet¹

¹Department of Neuropathology, Sainte‐Anne Hospital, Paris, France; ²Paris V Descartes University, Paris Cite Sorbonne, France; ³Department of Cancer Biology, Dana‐Farber Cancer Institute, Boston, Massachusetts 02115, USA; ⁴Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; ⁵UMR8203 Vecterologie et therapeutiques anticancereuses, Centre National de la recherche Scientifique, Gustave Roussy, Universite Paris Sud, Universite Paris saclay, 94805 Villejuif, France; ⁶Department of Paediatric Neuroradiology, Necker Enfants Malades Hospital, Paris, France; ⁷Department of Paediatric Neurosurgery, Necker Enfants Malades Hospital, Paris, France; ⁸APHM, Hopital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France

Introduction: Dysembryoplastic neuroepithelial tumor (DNT) belongs to low‐grade neuroepithelial tumors, which encompasses a large spectrum of tumors including recently genetically described entities. DNTs include three histopathologic subtypes described before the molecular biology era (simple/complex specific DNT [spe‐DNT], non‐specific DNT [ns‐DNT]). Rare progressive DNTs have been reported. The classification scheme for these tumors still needs to be clarified using the recent molecular advances.

Methods: We searched for BRAFV600E, FGFR1 mutations and FGFR1 tyrosine‐kinase domain internal tandem duplication (FGFR1‐ITD) by digital PCR in 82 DNTs, including 22 progressive spe‐DNTs confirmed by imaging review. Negative cases were further analyzed by RNAsequencing and whole‐exome sequencing. The tumors were classified by DNA‐methylation profiling. A correlation to the histopathology and imaging was performed.

Results: 35 tumors (45%) showed FGFR1 disruption (mutation/structural variants [SV]), including two FGFR1‐TACC1 fusions. No BRAF mutation was observed in spe‐DNT. Among ns‐DNT, BRAF (mutation/SV) and MYBL (SV) were the most frequently altered genes. Two cases harbored a novel fusion, FGFR2‐INA. By DNA‐methylation profiling, 92% of spe‐DNTs and 19% of ns‐DNTs clustered in the LGG‐DNT subgroup. At relapse, specific‐DNTs continued to cluster in the LGG‐DNT subgroup but harbored numerous copy number changes. These tumors showed contrast enhancement either at diagnosis or throughout disease progression.

Conclusion: Spe‐DNTs, with or without FGFR1 disruption, can be progressive and the genomic alterations that cause these DNTs to grow must be elucidated to adapt current therapeutic strategies. The ns‐DNT histopathologic subtype corresponds to a biologically heterogeneous group of tumours including the newly genetically identified entities.

P3‐64

A clinicopathological study of desmoplastic infantile gangliogliomas with analysis of BRAF and H3F3A gene alterations

Aruna Nambirajan; Prit Benny Malgulwar; Vaishali Suri; Chitra Sarkar; Mehar Chand Sharma

Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Original Study: Nambirajan A, Malgulwar PB, Suri V, Sarkar C, Sharma MC Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029 A clinicopathological study of desmoplastic infantile gangliogliomas with analysis of BRAF and H3F3A gene alterations

Introduction: Desmoplastic infantile gangliogliomas (DIG) are benign glioneuronal tumors characterised by a desmoplastic stroma. Despite Grade I histology, nearly 40% patients have complicated clinical course. Recently BRAF alterations have been described in other glioneuronal tumors. Limited data is available in DIGs due to its rarity.

Methods: Retrospective analysis (7 years) during which all DIGs were retrieved. Sequencing for BRAF and H3F3A gene mutations and real time PCR for BRAF fusions and gain were performed.

Results: A total of 4 DIGs were diagnosed over a 7 year period (0.001% of all brain tumors). All were male infants with age ranging from 8‐12 months. Histopathology showed desmoplastic leptomeningeal component in all cases with an appreciable small round cell component in one cases. MIB‐1 labelling indices ranged from 1% to 4%. On sequencing, BRAF gain was identified in one case, while BRAFV600E mutation, KIAA1549‐BRAF fusions or H3F3A mutations were absent. Two cases, including one with BRAF gain showed diffuse positivity for pS6kinase, indicating mTOR pathway activation.

Conclusion: Our study for the first time demonstrates the occurrence of BRAF copy number gain in DIG, suggesting BRAF gain in the absence of BRAFV600E mutation in DIGs may lead to aberrant m TOR signalling. These tumors may be potential candidates for BRAF therapy.

P3‐65

Chordoid glioma: a case at an uncommon location

Amanda Kan

Department of Pathology, Tuen Mun Hospital, Hong Kong SAR

Case Report: Kan A1 1 Department of Pathology, Tuen Mun Hospital, Hong Kong SAR Chordoid glioma: a case at an uncommon location

Introduction: Chordoid glioma is mostly described in the literature as a low grade glioma in the third ventricle. We encountered a myxoid neoplasm in the fourth ventricle resembling chordoid glioma.

Clinical summary: A 51‐year‐old lady complaint of 3 year history of unsteady gait and the MRI revealed a 3cm partially cystic enhancing lesion within the fourth ventricle associated with prominent hydrocephalus.

Pathological findings: Histology shows a myxoid neoplasm containing isolated or cords of eosinophilic tumour cells with occasional intracytoplasmic vacuoles and mild lymphocytic infiltrate. The tumour cells are diffusely immunopositive for vimentin, S100 and olig 2 while focally positive for EMA while negative for GFAP, CD34, TTF1, PR, brachyury, IDH1, D2‐40 and SSTR2.

Conclusion: We report a myxoid neoplasm most in keeping with chordoid glioma in an uncommon site.

P3‐66

MYB‐QKI rearrangement in Angiocentric glioma: a study in Chinese population

Fang Lian; Yong‐Juan Fu; Yue‐Shan Piao; De‐Hong Lu

Department of Pathology, XuanWu Hospital, Capital Medical University

Introduction: To evaluate the diagnostic value of MYB‐QKI in Angiocentric glioma (AG) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

Methods: Twenty‐six AG samples were collected from five hospitals, and MYB protein expression was detected by IHC, MYB‐QKI rearrangement was detected by FISH, then MYB‐QKI status and clinicopathological association were analyzed.

Results: All 26 patients had a history of refractory epilepsy with a mean history of 12 years and a median age at surgery of 18 years. The AG lesions were located in superficial cerebrocortical locations. Except for the classical histological features, the involvement of superfacial cortex extending to the leptomeninges, microcalcification, and the cystic pattern with microcystic formations were observed in 42.3% (11/26), 11.5% (3/26) and 15.4% (4/26), respectively. In all 26 cases, the IHC positive rate of GFAP, Vimentin, NeuN, EMA, D2‐40, MYB, IDH1R132H, BRAF V600E, L1CAM, H3K27M were 100% (26/26), 100% (26/26), 0% (0/26), 84.6% (22/26), 76.9% (20/26), 50% (13/26), 0% (0/26), 0% (0/26), 0% (0/26), 0% (0/26), respectively. The Ki‐67 labeling index was 1‐5% in 24 cases, the other 2 cases was 10% and 20%. The positive rate of MYB‐QKI rearrangement with FISH was 95.7% (22/23) in AGs.

Conclusions: The study showed that FISH was more appropriate for MYB‐QKI rearrangement detection. MYB‐QKI rearrangement was confirmed in majority of AGs, which may act as potential diagnostic biomarker for AGs.

P3‐67

Rosette‐Forming Glioneuronal Tumors: A Small Case Series

Nelli S Lakis; Kathy L Newell

Department of Pathology, University of Kansas Medical Center

Introduction: Rosette‐forming glioneuronal tumor (RGNT) is a rare, WHO grade I tumor originally included in the 4th edition of the World Health Organization (WHO) classification of tumors of the CNS and included in the revised editions (2007, 2016). Thought to arise exclusively in the 4th ventricle, it has been described in the pineal gland, septum pellucidum, lateral ventricle and thalamus.

Methods: A retrospective review of the neurosurgical files at The University of Kansas Medical Center from 2011 to 2018 using the following search items was performed: “rosette” and “glioneuronal” in the “final diagnosis” and/or the “diagnosis comment”. Cases that met the current WHO 2016 criteria were included. Radiographic findings and long‐term follow up were correlated for each case.

Results: Five cases were retrieved. Clinically, all were female, age ranging from 18 ‐ 56 (average 36.6). Tumor locations included left posterior cerebellum, 3rd ventricular mass, cerebellar vermis, and two 4th ventricular masses. Clinical presentations included hydrocephalus, incidental lesions discovered on imaging, and dizziness and headaches. Clinical follow up ranged from 2 to 66 months and all lesions are stable and have caused no further concern. Radiographically, two of the lesions showed T2 hyperintense, T1 hypointense and nonenhancing lesions, as described in the WHO 2016. Two lesions were cystic with patchy enhancement, and another was cystic and non‐enhancing.

Conclusion: Rosette‐forming glioneuronal tumors are rare WHO grade I lesions with bland histology and excellent long‐term follow up. Originally described in the 4th ventricle, the unique histology may also be seen in other locations.

P3‐68

A case of rosette‐forming glioneuronal tumor with an increased MIB‐1 labeling index and mitotic figures in glial component

Naoe Jimbo¹; Takashi Sasayama²; Kazuhiro Tanaka²; Takanori Hirose³

¹Department of Diagnostic pathology, Kobe University Graduate School of Medic ine, Kobe, Japan; ²Department of Neurosurgery, Kobe University Graduate School of Medicine, Kob e, Japan; ³Department of Diagnostic pathology, Hyogo Cancer Center, Akashi, Japan

Rosette‐forming glioneuronal tumors (RGNT) is a rare tumor of WHO grade I commonly arising in the fourth ventricle or cerebellum of young adults. Histologically they are characterized by a biphasic pattern consisting of well‐differentiated neurocytic rosettes and pilocytic astrocytoma‐like areas. This tumor behaves indolently, though postoperative deficits may occur. Here we report a case of RGNT, which showed an increased MIB‐1 labeling index and mitotic figures in glial component. The patient is a 19‐year‐old male who visited a doctor for a head trauma in June 2015. CT scan incidentally demonstrated a 15 mm tumor in the midbrain and ventricular enlargement. The biopsy revealed proliferation of astrocytic cells with fibrillary matrix and neurocytic cells often arranged in rosettes. The latter were positive for synaptophysin. MIB‐1 index was an extremely low (0.3%). These pathologic findings led to the diagnosis of RGNT. One and a half years later, tumor growth (30 mm) and hydrocephalus appered and rebiopsy was performed. Microscopic features were almost identical to those of the first biopsy specimen; however, mitotic figures was observed at maximum 2/10 HPF and a MIB‐1 index was 30% in the glial component. At present (May 2018), the tumor did not show significant growth (33 mm). Although RGNT is considered to be benign, glial cells of this tumor occasionally may exhibit an increased proliferative activity like our case. It is necessary to carefully follow up the clinical course of those RGNT.

P3‐69

A case of spinal rosette‐forming glioneuronal tumor

Mishie Tanino¹; Shuji Hamauchi²; Hirokazu Sugino³; Masumi Tsuda³; Hidehiro Takei¹; Shinya Tanaka³

¹The Department of Surgical Pathology, Asahikawa Medical University; ²Hokkaido University Faculty of Medicine, Department of Neurosurgery; ³Hokkaido University Faculty of Medicine, Department of Cancer Pathology

Rosette‐forming glioneuronal tumor (RGNT) is a rare tumor which was first reported as the fourth ventricle tumor by Komori, et al. and is classified as a distinct clinicopathological entity by the WHO Classification of Tumors of the Central Nervous System as of 2007. Although RGNTs were reported to occur in both supratentorial and inflatentorial sites, only four case reports of spinal RGNT have been demonstrated. This case report describes an RGNT arising from the cervical spinal cord with unique pathological features including the results of molecular analysis, which occurred in a 37‐year‐old female. Magnetic resonance imaging revealed an intramedullary mass at C1 to C5, which was totally resected. Pathological analysis showed a unique biphasic cellular architecture consisting of perivascular pseudorosettes dominantly with few neurocytic rosettes and diffuse astrocytoma component. The tumor cells composed of perivascular pseudorosettes showed positivity for both synaptophysin and olig2. In the genetic analysis, neither IDH1/2, FGFR1, BRAF, PIK3CA mutations nor 1p19q codelletion were found. We review the relevant literature and summarized the clinical course including the treatment and prognosis, pathological features and molecular features of spinal RGNT.

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A glioneuronal tumor with intermediate feature between rosette‐forming glioneuronal tumor (RGNT) and pilocytic astrocytoma (PA) harboring FGFR1 mutation: consideration of ‘RGNT‐PA sequence’

Seiji Yamada¹; Takao Teranishi²; Sadakatsu Watanabe³; Kazuhiro Murayama⁴; Shigeo Ohba²; Tatsuya Yamazaki⁵; Sumihito Nobusawa⁵; Yuichi Hirose²; Hideaki Yokoo⁵; Masato Abe⁶

¹Department of Diagnostic Pathology, Fujita Health University, Toyoake, Japan; ²Department of Neurosurgery, Fujita Health University, Toyoake, Japan; ³Department of Comprehensive Strokology, Fujita Health University, Toyoake, Japan; ⁴Department of Diagnostic Radiology, Fujita Health University, Toyoake, Japan; ⁵Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan; ⁶Department of Pathology, School of Health Sciences, Fujita Health University, Toyoake, Japan

Introduction: Rosette‐forming glioneuronal tumor (RGNT) is a rare glioneuronal tumor that preferentially arises in the fourth ventricle in young adults. Although the tumor has many similarities to pilocytic astrocytoma (PA) both histologically and genetically, its histogenesis is largely still unknown. We report a case of PA‐like glioneuronal tumor including a tiny amount of glioneuronal rosette‐like component harboring FGFR1 mutation.

Clinical Summary: A 16‐year‐old female presenting with absence seizures. MRI revealed a right temporal lobe mass with low T1 and high T2/FLAIR signals and a multinodular enhancing by gadolinium administration. A macroscopic total tumor resection was performed.

Histological Findings: Most of the tumor was composed of round to oval oligodendrocyte‐like cell (OLC) with variable perinuclear haloes. Abundant Rosenthal fibers and eosinophilic granular bodies were identified. Mitoses and necroses were absent. Focal neurocytic rosette feature, which exhibits ring‐like arrays of OLC around delicate eosinophilic neuropil cores, were observed. Massive hemosiderin depositions were seen in the superficial layer of the cortex, which were consistent with superficial siderosis.

Mutational Findings: Direct sequencing revealed a missense mutation in FGFR1 exon 14 (K656F), whereas FGFR1 exon 14 (N546K), PIK3CA exon 9 (E542K), PIK3CA exon 20 (H1047R), BRAF codon 600 were intact. A KIAA1549‐BRAF fusion was not detected by FISH analysis.

Discussion: This tumor possessed intermediate characteristics between RGNT and PA both histopathologically and genetically. These similarities might suggest consideration of ‘RGNT‐PA sequence’ as a concept.

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Clinical and molecular features of two cases of rosette‐forming glioneuronal tumor at midbrain

Ichiyo Shibahara¹; Mitsuru Dan¹; Kazuhiro Miyasaka¹; Sumito Sato¹; Takuichiro Hide¹; Takako Yoshioka²; Junko Hirato³; Yoshiko Nakano⁴; Koichi Ichimura⁴; Toshihiro Kumabe¹

¹Department of Neurosurgery, Kitasato University School of Medicine, Kanagawa, Japan; ²National Center for Child Health and Development, Tokyo, Japan; ³Gunma University Hospital, Gunma, Japan; ⁴National Cancer Center, Tokyo, Japan

Background: We experienced two cases of rosette‐forming glioneuronal tumor (RFGT) at midbrain. In this study, we discussed the clinical, histological, and molecular features of RGFT at midbrain.

Cases: One case was 18 year‐old male presented with right upper limb hemiparesis, and the other case was 23 year‐old female presented with left hemisensory disturbance. Tumors were located at midbrain and showed ring‐enhancement by gadolinium‐enhanced T1‐weighted magetic resonance imaging. A partial removal was conducted through the occipital transtentorial approach in each case. Histologically, HE staining demonstrated biphasic pattern of neurocytic and glial architecture. The former structure consists of neurocytic rosettes and perivascular pseudorosettes with positivity for synaptophysin. The other immunohistochemical staining demonstrated GFAP‐positive, IDH1R132H‐negative, and 2‐3% of MIB‐1 labeing lindex, thus the diagnosis with RFGT was made.

Discussion: RFGT is categorized in WHO grade I, and its incidence is reported to be very rare. RFGT usually arise in the fourth ventricle. Several reports also demonstrated RFGT at brain stem. Histologically, RGFT resembles ependymoma and pilocytic astrocytoma, and the key for the diagnosis is the presence of neurocytic architecture. Genetically, the involvement of PI3KCA and FGFR1 gene mutations are reported. Molecular analysis of the current two cases is under investigation.

Conclusion: Brain tumor at midbrain is rare, and RFGT needs to be considered as a differential diagnosis.

P3‐72

A case of atypical central neurocytoma with Rosettes and relatively rapid growth

Naokazu Hayashi¹; Yoichi Nonaka¹; Jun Nishiyama¹; Chie Inomoto²; Naoya Nakamura²; Mitsunori Matsumae¹

¹The department of Neurosurgery, Tokai Univercity school of Medicine, Isehara, Japan; ²The department of Pathology, Tokai Univercity school of Medicine, Isehara, Japan

Central neurocytoma is a rare tumor and is considered to be 0.25‐0.5% of the intracranial tumor. Although the growth is slow, there are reports that some cases show anaplastic property and some cases have high proliferative potential. Also, normally rosette is not observed. We report a case of Atypical central neurocytoma which had increased relatively rapidly before surgery and was observed Rosette. A 21‐year‐old man was introduced to examine mass lesions adhering to the left lateral ventricle sidewall, which was discovered in headache scrutiny. The lesion was not accompanied by calcification, MRI showed high signal in T2 weighted image, ADC was low, contrast effect was poor. As a distinction on images, Subependymoma, Central neurocytoma was considered. Since the diameter increased from 12 mm to 19 mm in the course of six months, it was a surgical plan. The tumor was soft and easy to bleed. Adhesion / infiltration findings with the ventricular wall were observed . Total tumor was removed. In intraoperative consultation, Ependymoma was thought to be due to the increase of compact circular nucleus and acidophilic body and Rosettes. Immunohistochemical study showed positive Synaptophysin. EMA, Chromogranin A, NFP and OLG 2 were negative. Although we could not point out angiogenesis or necrotic image, three or more nuclear fission images were recognized per High‐Power Field. And the Ki ‐ 67 labeling index was 6.5%. Because it was a diagnosis of Atypical central neurocytoma, it is considered as radiation irradiation at the time of recurrence.

P3‐73

Growing papillary glioneuronal tumor (PGNT) with solid components: A case report

Kazuma Shinno¹; Yoshiki Arakawa¹; Sachiko Minamiguchi²; Masahiro Tanji¹; Yohei Mineharu¹; Takayuki Kikuchi¹; Susumu Miyamoto¹

¹Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; ²Department of Diagnostic pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Papillary glioneuronal tumor(PGNT)is classified as one of mixed neuronal‐glial tumors, WHO grade I. Most PGNT is accompanied with cystic formation in the cerebral hemisphere, mainly in youth. Here we report a 38 year‐old man with growing papillary glioneuronal tumor without cyst formation and epilepsy for 11 years after the first diagnosis. In his past history, he had undergone surgery for arachnoid cyst. MRI at the initial visit showed that it was 14mm in the major axis in precentral gyrus and hypointense in T1W1 and hypointense in T2W1 with a gadolinium‐enhanced spot. Subsequent MRI studies showed the slow growth of tumor and its enhancement associated with surrounding brain edema for 11 years. He underwent tumor resection to identify its pathology. The histopathological study revealed that the tumor was composed of neuronal and glial tumor cells showing pseudopapillary architecture with hyalinized blood vessels. Neuronal and glial tumor cells have oval nucleus with acidophilic cytosol. Rosenthal fibers and acidophilic granules were also observed. Immunohistochemical analysis showed that the neuronal component was positive for synaptophysin and NeuN, and that the glial was positive for Olig2 and GFAP. Based on these findings, it was diagnosed as papillary glioneuronal tumor.

P3‐74

High‐grade glioneuronal tumor with NTRK fusion: a case report

Kazuhiko Kurozumi¹; Yoshiko Nakano²; Joji Ishida¹; Takehiro Tanaka³; Masatomo Doi⁴; Junko Hirato⁵; Akihiko Yoshida⁶; Koichi Ichimura⁶; Hiroyuki Yanai¹; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ²Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan; ³Department of Pathology, Okayama University Hospital, Okayama, Japan; ⁴Division of Pathology, St. Marianna University School of Medicine, Japan; ⁵Clinical Department of Pathology, Gunma University Hospital, Gunma, Japan; ⁶Department of Pathology, National Cancer Center Hospital, Tokyo, Japan

Here, we present a rare case of high‐grade glioneuronal tumor with Neurotrophic Tyrosine Kinase Receptor (NTRK) fusion. A 13‐year‐old girl presented with headache and vomiting. Computed tomography showed a left frontal cystic lesion and hydrocephalus, with calcified cystic lesions in the contralateral hemisphere. Magnetic resonance images detected a solid lesion and enhanced cystic components. We performed a left frontal craniotomy to remove the tumor and provide ventricular drainage. She was initially treated with temozolomide as anaplastic oligodendroglioma. During follow up, this tumor recurred and was resected again. Moreover, we added radiation therapy. Histological findings showed small, hypervascular, spindle‐shaped astrocytic components, but no endothelial proliferation or necrosis. The specimen also included round cells with perinuclear halos. These round cells and the ganglioid cells were found in the recurred area. Immunohistochemistry showed the cells to be partially GFAP+, Olig2+, NeuN‐, synaptophysin+, mIDH1‐, and ATRX. The MIB‐1 labelling index was approximately 20% in initial lesion, and 54% in recurrent area. In both specimens, direct sequencing showed IDH1/2, H3F3A (K27 and G34), and BRAFV600E were not mutated; however, FISH and MLPA showed a 1p19q codeletion. In central pathology review this case was finally diagnosed as high grade glioneuronal tumor. RNA sequencing identified a fusion gene, ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)‐NTRK1. From these genomic findings, we diagnosed a glioneuronal tumor with NTRK fusion. Detecting this fusion gene may become important in stratifying subjects in future clinical trials with NTRK inhibitor.

P3‐75

Lymphocytic Hypophysitis with hypertrophic intracranial pachymeningitis: a case report

Katsuhide Tai¹; Takahiro Yamauchi¹; Ryuhei Kitai¹; Shohei Higuchi²; Kunihiro Inai³; Yoshiaki Imamura²; Ken‐ichiro Kikuta¹

¹Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; ²Division of Surgical Pathology, University of Fukui Hospital, Fukui, Japan; ³Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

We report a case of lymphocytic hypophysitis with hypertrophic intracranial pachymeningitis. Case: A 44‐years‐old man presented with headache and was referred to our department. His laboratory investigations revealed panhypopituitarism due to a pituitary mass lesion. Magnetic resonance imaging (MRI) showed a sellar mass and thickening of the pituitary stalk and dura with contrast media dumbbell shaped suprasellar. He was given 15mg daily of hydrocortisone for hypoadrenalism. The lesions were not responded during glucocorticoid treatment for 6 months. Biopsy was done via transsphenoidal approach. Histopathological examination showed massive infiltrating lymphocyte and fibrosing pituitary glands. Immunohistochemical staining revealed B lymphocytes were dominantly infiltrated. Thickend dura mater were also same pathological findings. Lymphocytic hypophysitis were known as T cell predominance and responded to steroid therapy. This case is unique that B cell were conspicuous and hypertrophic pachymeningitis.

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A case of WHO grade I meningioma metastasized to the lung 26 years after initial surgery

Toshiyuki Enomoto^1,2; Mikiko Aoki¹; Yuki Kouzaki²; Hiromasa Kobayashi²; Reona Yamamoto³; Naoko Imamura³; Masani Nonaka²; Hiroshi Abe²; Tooru Inoue²; Kazuki Nabeshima²

¹Department of Pathology, Faculty of medicine Fukuoka University, Fukuoka, Japan; ²Department of Neurosurgery, Faculty of medicine Fukuoka University, Fukuoka, Japan; ³Department of General Thoracic, Breast, and Pediatric Surgery, Faculty of medicine Fukuoka University, Fukuoka, Japan

Back ground: Meningiomas comprise 13‐26% of all intracranial tumors, and are usually slow growing and benign. Distant metastasis of a meningioma is rare and associated with WHO grade II or III meningiomas; metastasis from grade I is especially rare.

Case: A 65 year old male underwent surgery for posterior fossa meningioma WHO grade I 26 years ago at another hospital. Eleven years ago, the tumor recurred and γ‐knife radiosurgery was performed. Seven years ago, the tumor recurred again, and he attended our hospital for the second surgery. The tumor was totally excised (Simpson grade II) and histology indicated meningioma WHO grade I. Before admission to our hospital he had suffered headaches and vomiting for four months. The tumor had recurred in the same area and extended from the margin of the previous excisional site to the right middle cranial fossa. Tumor resection was performed after feeder occlusion. Histology again indicated meningioma WHO grade I. Preoperative examination revealed a nodule in the lower lobe of the right lung. Because this nodule gradually grew larger, partial resection of the right lower lobe was performed four months after the third operation. Although the tumor showed a central necrosis, its histology was consistent with meningioma WHO grade I.

Conclusion: Metastasis of meningioma WHO grade I is rare. Grade I histology of the metastatic site is also rare. We discuss our case and review relevant literature.

P3‐77

The case of lymphoplasmacyte‐rich meningioma invaded to sigmid sinus

Masatomo Doi¹; Yasuyuki Yoshida²; Hidetaka Onodera³; Daisuke Wakui³; Homare Nakamura³; Yotaro Sakakibara³; Nobuyuki Yanagisawa⁴; Masayuki Takagi¹; Yuichiro Tanaka⁵

¹Department of Pathology, St. Marianna University School of Medicine; ²Department of Neurosurgery, St. Marianna University School of Medicine Toyoko Hospital; ³Department of Neurosurgery, St. Marianna University School of Medicine Yokohama City Seibu Hospital; ⁴Department of Pathology, St. Marianna University School of Medicine Yokohama City Seibu Hospital; ⁵Department of Neurosurgery, St. Marianna University School of Medicine

Lymphoplasmacyte‐rich meningioma (LPRM), the most rare variant of meningiomas, features extensive lympjoplasmacytic infiltrates. We present an extremely rare case of LPRM extended to sigmoid sinus. 72‐year‐old woman had complaint right visual activity loss. Neurological examination disclosed right visual activity and visual field loss. The magnetic resonance imaging revealed the homogeneous enhancement mass lesion extended in the right middle base to cerebellar tent measuring 25mm in diameter with invaded sigmoid sinus, suggesting meningioma. The operation was performed. The tumor was elastic hard compare to normal meningioma and adhesive to arachnoid strongly. After the operation, the patient's visual activity loss was also improved. Histologically, the tumor showed dense infiltration of lymphocytes and plasma cells with occasional formation of lymphoid follicles. We also found focal collection of epithelioid cells that showed whorl formation and immunoreactivity for epithelial membrane antigen (EMA). These collective findings led us diagnose this tumor as LPRM. The Ki‐67 LI was higher than benign meningioma about 10%. The local recurrence of the tumor was not detected at follow‐up. LPRM is the most rare variant of meningiomas, classed WHO grade 1 as benign tumor. The neuro‐imaging shows thicked enhancement of the dura matter, likes hypertrophic pachymeningitis. The pathological findings features extensive lympjoplasmacytic infiltrates and poor tumor progression. The present case shows typical neuro‐imaging and pathological findings, but invaded to sigmoid sinus and higher Ki‐67 LI. Since the natural history of this tumor is unclear and reported the recurrent case, careful follow‐up is needed.

P3‐78

Diagnosis changed from Angiomatous meningioma to solitary fibrous tumor / hemangiopericytoma by molecular analysis

Yukiko Nakahara¹; Motofumi Koguchi¹; Tomihiro Wakamiya¹; Jun Masuoka¹; Yukari Takase²; Shamakhi Aishima²; Tatsuya Abe¹

¹Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan; ²Department of Pathology, Saga University Hospital, Saga, Japan

Since both SFT and HPC fuse the NAB2 and STAT6 genes and leads to STAT6 nuclear expression, the 2016 WHO classification has created the combined term. We report a case of multiple brain tumors which was changed its diagnosis by IHC from angiomatous meningioma (AM) to solitary fibrous tumor / hemangiopericytoma(SFT/HPC). A 59‐year‐old male was admitted to hospital for cognitive dysfunction. Magnetic resonance imaging revealed tumors measuring 70X68mm in the right frontal parasagittal and 16X15mm in the left frontal convexity. We performed the surgical removal of the right tumor and diagnosed as angiomatous meningioma(AM), grade I. Four years later after the surgery, the left side of tumor was growing with hemorrhage. The tumor was totally resected. Histological examination revealed the tumor composed of proliferation of spindly cells. Mitotic activity is over 4‐5 per 10 high power fields. Immunohistochemical(IHC) studies revealed positivity with CD34, and negative results for S‐100 and EMA. STAT6 was positive in nuclear of tumoral cells. The tumor of left side was diagnosed with SFT/HPC, grade III. We investigated the previous tumor of the right side. According to IHC, the tumoral cells revealed the nuclear positivity with STAT6. The diagnose was changed to SFT/HPC from AM. The molecular biological studies were important for the differential diagnosis between SFT/HPC and AM.

P3‐79

Intracranial fibrosarcoma with somatic mutations in NF2 and ATRX

Takahide Nejo¹; Shunsaku Takayanagi¹; Shota Tanaka¹; Aya Ushiku²; Shinji Kohsaka³; Shigeo Sora⁴; Hiroyuki Aburatani⁵; Hiroyuki Mano³; Akitake Mukasa⁶; Nobuhito Saito¹

¹Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ²Department of Pathology, The University of Tokyo, Tokyo, Japan; ³Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; ⁴Department of Neurosurgery, Tokyo Metropolitan Police Hospital, Tokyo, Japan; ⁵Genome Science Division, RCAST, The University of Tokyo, Tokyo, Japan; ⁶Department of Neurosurgery, Kumamoto University, Kumamoto, Japan

Background: Clinical sequencing has greatly gained prevalence and can facilitate clinical decision‐making and understanding of pathogenesis in challenging cases. Herein, we report a case with an intracranial fibrosarcoma, wherein the clinical panel sequencing (‘Todai OncoPanel’ [TOP]) and DNA methylation analysis yielded additional information.

Clincal Summary: A 69‐year‐old female presented with an intraparenchymal hemorrhage in the right frontal lobe. Additional examinations led to the diagnosis of tumor bleeding suspect of meningioma. While she underwent a near‐total tumor resection, we observed discontinuity between the tumor and falx cerebri. Although the postoperative course was initially favorable, the residual tumor displayed a rapid regrowth just two and a half months later. Accordingly, she underwent a second surgery, followed by chemoradiotherapy. To date, the tumor remains under control for eight months.

Pathological Findings: Primary and recurrent tumors shared similar histological findings: tumors comprised of dense, spindle‐shaped cells with pale, eosinophilic cytoplasm arranged in interlacing fascicles. Additionally, mitoses were frequently observed (1‐4/high‐power field). Immunohistochemistry for EMA, PgR, STAT6, GFAP, HMB‐45, S‐100 stained all negative. Consequently, the diagnosis of an intracranial fibrosarcoma was made. Besides, the TOP analysis detected somatic mutations in NF2 and ATRX. Copy number analysis revealed MDM2 gain and loss of heterozygosity on chromosome 22q. Furthermore, clustering analysis on DNA methylation status combined with public data revealed the similarity with highly aggressive sarcoma.

Conclusions: We describe a case with an intracranial fibrosacroma. Along with clinical panel sequencing and DNA methylation analysis, this study will shed light on this rare entity.

P3‐80

A rare case of craniopharyngioma with malignant transformation

Naoe Jimbo¹; Taniguchi Masaaki²; Takanori Hirose³

¹Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; ²Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Japan; ³Department of Diagnostic Pathology, Hyogo Cancer Center, Akashi, Japan

Craniopharyngioma is a benign tumor belonging histologically to WHO grade I. Malignant transformation of this tumor is extremely rare. Here, we report a case considered as craniopharyngioma with malignant transformation. The patient is a 30‐year‐old female who was initially diagnosed at age 14 as a sellar/suprasellar typical adamantinomatous craniopharyngioma in 2001. She had repeatedly received surgery 8 times, radiation therapy (2001), and gamma knife radiation therapy twice (2005, 2008) for multiple recurrences. From the primary tumor to sixth recurrence (2013), histological findings showed a typical adamantinomatous craniopharyngioma. However, from the 7th recurrence (2015), high cellularity and increased number of mitotic figure and MIB‐1 index were observed gradually. At the 9th recurrence, the number of mitotic figure increased to 11/10 HPF. There are only a few reports of malignant craniopharyngioma and no clear criteria for malignant transformation have been established. However, at least the 9th recurrent tumor was considered to be malignant. She received postoperative radiotherapy. At present (May 2018), there is no tumor growth although tumor remains. Several reports suggested that the effects of radiation therapy are one of the possibilities for malignant transformation, but the mechanism remains to be clarified. As the prognosis of malignant craniopharyngioma is considered to be extremely poor, accurate prediction of prognosis and discussion of additional treatment are necessary, and it is desirable to construct appropriate criteria of malignancy in craniopharyngioma.

P3‐81

A case of methotrexate associated lymphoproliferative disorders

Kenichi Sato¹; Taku Asanome¹; Yoshimaru Ozaki¹; Yuuki Ishida¹; Hirohiko Nakamura¹; Hirokazu Sugino²; Shinya Tanaka²

¹Department of neurosurgery, Brain tumor center, Nakamura Memorial Hospital, Sapporo, Japan; ²Department of Cancer Pathology Hokkaido University Faculty of Medicine

Introduction: Methotrexate (MTX) plays an important role in the treatment of rheumatoid arthritis (RA) but reports on lymphoproliferative diseases (LPD) associated with the use of MTX have been increasing in recent years. We report cases of central nervous system lymphoproliferative diseases due to methotrexate related lymphoproliferative disease (MTX ‐ LPD).

Case: A 75‐year‐old female. She visited us with complaints of cerebral movement disorder and gait disturbance on the right hand two weeks ago. MRI revealed 3 cm neoplastic lesions in left parietal lobe.

Surgical findings: The lesion was exposed to the brain surface and was elastic hard. The boundary with normal tissue was relatively clear, mainly composed of granulomatous necrotic tissue. Lesions were completely excised.

Pathological diagnosis: The invasion of inflammatory cells and the proliferation of heteromorphic cells of the lymphoid lineage were observed. Heterotypic cells are GFAP negative, olig 2 negative, IDH 1 negative, CD 3 partial positive, CD 20 partial positive, EBER ‐ ISH partially positive. MIB 1 index is about 40% by hot spot. ALK ‐ 1 negative. It was thought to be diffuse large B cell lymphoma than morphology and trait. In the last 7 years ago MTX was continuously administered to RA and oligoclonality was confirmed by IgH rearrangement, it was diagnosed as central nervous system lymphoma by MTX‐LPD.

Conclusion: Although the report of MTX ‐ LPD has been increasing in recent years, there are not many cases reported in the central nervous system. We reported to share experiences of rare cases.

P3‐82

A case of primary central nervous system T‐cell lymphoma seems to be caused by long‐term administration of adalimumab

Yutaka Fuchinoue; Chie Matuura; Shinichi Okonogi; Yasuhiro Node; Shunpei Ando; Hiroyuki Masuda; Kosuke Kondo; Naoyuki Harada; Nobuo Sugo

Department of Neurosurgery (Omori), School of Medicine, Faculty of Medicine, Toho University

Many of primary central nervous system lymphoma (PCNSL) are diffuse large B‐cell lymphoma and T cell lymphoma is rare. we report a case of primary central nervous system T‐cell lymphoma seems to be caused by long‐term administration of adalimumab. A 41‐year‐old male was suffering from Headache, nausea and dizziness 2 weeks before admission. He was administered adalimumab for Crohn ‘s disease from 6 years ago. CT showed a tumor in the right cerebellum. At the time of admission, Japan Coma Scale I ‐1 and no neurological abnormal findings were observed. MRI revealed a 44 x 40 mm tumor in the right cerebellum that was ring‐enhanced with gadolinium. The day6, his consciousness got worse because of rapid deterioration of hydrocephalus, then tumor resection by craniotomy was performed. Histopathological findings showed proliferation of atypical lymphocytes which are CD3 (+), CD4 (+), CD5 (+), CD20 (‐), therefore we diagnosed peripheral T cell lymphoma. Postoperatively, consciousness disturbance was improved. Adalimumab is known to increase the risk of developing malignant tumors such as lymphoma during long‐term administration to children and young adults. Considering that susceptible age for PCNSL is 50‐70s and T cell lymphoma is rare, this case seems to be caused by long‐term administration of adalimumab. Using TNF antagonists such as adalimumab may occasionally causes complications of PCNSL, therefore we need careful follow‐up.

P3‐83

A case of central nervous system methotrexate‐associated lymphoproliferative disorders (MTX‐LPD)

Yuuki Ishida¹; Kenichi Sato¹; Yoshimaru Ozaki¹; Taku Asanome¹; Hirohiko Nakamura¹; Hirokazu Sugino²; Shinya Tanaka²

¹Department of neurosurgery, Brain tumor center, Nakamura Memorial Hospiral, Spporo, Japan; ²Department of Cancer Pathology Hokkaido University, Sapporo, Japan

Introduction: Methotrexate (MTX) is one of the central drugs in the treatment of RA and other autoimmune diseases, but its report of MTX‐related lymphoproliferative disease (MTX‐LPD) has increased. Here we report one case of central nervous system lymphoproliferative disorder by MTX‐LPD.

Case: A 65‐year‐old woman. We visited our hospital with complaints of dysphagia, diplopia and gait disturbance two weeks ago. MRI revealed a 2 cm tumor massive from the left medullar to the left cerebellar limb with contrasting margin. Tumors were also found in soft tissues around the left femur and subcutaneous tissues such as inguinal lymph nodes. Since 7 years ago MTX was orally administered to palmoplantar cystic disease, MTX‐related lymphoproliferative disease was suspected and left hip tumor mass was biopsied.

Pathological diagnosis: Large heteromorphic cells with enlarged nucleus proliferated diffusely, and nuclear fission images were scattered. Heterotypic cells showed CD20 positive, CD3 negative, EBER ‐ ISH negative, and the Ki ‐ 67 labeling rate was 80%, which was diagnosed as Diffuse large B ‐ cell lymphoma.

Progression: After diagnosis, oral administration of MTX was stopped and treated with steroids. Cerebellar lesions and subcutaneous masses also shrunk and symptoms improved.

Conclusion: A tumor of the whole body including the central nervous system disappeared due to discontinuation of MTX administration, and a case of MTX‐LPD was reported. There are not many cases reported in the central nervous system. We reported to share experiences of rare cases.

P3‐84

Lymphomatoid granulomatosis of the brain: A case report

Kazuhiro Tanaka¹; Takashi Sasayama¹; Yuichi Fujita¹; Masahiro Maeyama¹; Naoe Jinbo²; Tomoo Itoh²; Takanori Hirose³; Eiji Kohmura¹

¹Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Japan; ²Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan; ³Department of Pathology for Regional Communication, Kobe University Hospital, Kobe, Japan

A 75‐year‐old male was followed every year for old cerebral infarction and unruptured cerebral aneurysm. Magnetic resonance imaging (MRI) of the brain unexpectedly revealed a mass with a large cerebral edema in the right frontal lobe, which was not found the year before. Neurological examination did not showed any symptoms. A computerized tomography (CT) scan did not demonstrated any other mass lesions. The patient was hospitalized and underwent a right frontal lobectomy using the Brainlab navigation system. Pathology reported polymorphous, CD20‐positive, Epstein‐Barr virus (EBV)‐positive, lymphohistiocytic, inflammatory infiltrate within the walls of the vessels with associated necrosis and diagnosed a lymphomatoid granulomatosis. The patient received no adjuvant treatments because of complete resection of tumor. Four months after his diagnosis, brain MRI showed no recurrence. Lymphomatoid granulomatosis is a rare disorder of the central nervous system (CNS) with few cases being reported in literature. We discuss the process of evaluation and management.

P3‐85

Reappraisal of multiple cerebral lesions characterized by dense T cell infiltration in patient with DLBCL in past history and PTCL‐NOS developing two years later

Kenji Sano¹; Midori Sato²; Shota Kobayashi²; Takeshi Uehara²

¹Department of Pathology, Iida Municipal Hospital, Nagano, Japan; ²Department of Laboratory Medicine, Shinshu University, Nagano, Japan

Case: 56 year‐old malePast history: DLBCL of tonsil in complete remission three years agoPresent history: He had general fatigue, intense daytime sleepiness and taste disorder. Multiple lesions located by MRI suggested primary lymphoma, lymphomatoid granuloma(LYG). Thorough investigation of blood, CSF, skin random biopsy etc. did not reveal definite diagnosis. The cerebral lesion removed by craniotomy disclosed dense small T cell infiltration in parenchyma, showing CD3 +, CD5 +, CD10‐, CD20+ (very few), CD4 < CD8, EBV‐ISH ‐. Relapse of DLBCL and LYG were unlikely diagnosis. Polyclonal pattern of TCRγ and B cell (CDRIII) clonality tests from the lesion suggested reactive infiltration. Steroid therapy was administered based on the possible diagnosis of Clippers syndrome. Some of the CNS lesions disappeared. Two years later, he developed PTCL‐NOS in bone marrow characterized by dense T cell infiltration and complex karyotype abnormalities. In retrospective evaluations, brain lesions were examined by the clue of specific karyotype abnormalities whether they can be regarded as an early lesion of PTCL‐NOS.

P3‐86

A case of cauda equina primary extramedullary plasmacytoma

Yoshitaka Oda¹; Hirokazu Sugino¹; Izumi Koyanagi³; Tanikawa Satoshi¹; Yuusuke Ishida¹; Masumi Tsuda^1,2; Shinya Tanaka^1,2

¹Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; ²Global Station for soft Matter, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan; ³Neurosurgery, Hokkaido Neurosurgery Memorial Hospital

Case presentation: 78 years old male patient had suffered from buttock and leg pain from 2016 and the symptoms had been progressed. He visited neurosurgeon and magnetic resonance imaging(MRI) as axial imaging showed swollen nerve of cauda equina, at levels of L4‐S1 and this lesion was diffusely enhanced with Gd. Lymphoma was mostly suspected by MRI features, but laboratory data such as value of LDH and sIL‐2 receptor were within normal range. Other differential diagnoses were myxopapillary ependymoma neurofibroma, metastatic spinal tumor, and infectious inflammatory disease including miliary tuberculosis.

Histopathological findings and disucssion: Tumor biopsy were performed in April 2018, and cauda equina were swollen and there were no involvement of spine. Histologically, neoplastic plasma cells which had axle‐like nuclear and a lot of Russel body were massively proliferated within the peripheral nerves of cauda equina, and the neoplastic cells were demonstrated immunohistochemical positivity for CD138 with Ig‐G kappa light chain restriction. CD20 and CD3 positive cells were small and had no atypia excluding malignat lymphoma, or negativity for AE1/AE3 suggested no metastatic carcinoma, and diagnosed as plasmacytoma. Extramedullary plasmacytomas account for about 4% of all plasma cell tumors. This tumor occurs mainly in upper gastrointestinal and respiratory tract, and also in lung, thyroid gland, orbita, and lymph node. Cauda equina is very rare region affected by primary extramedullary plasmacytoma, reported as 5 cases as literature previously in worldwide.

P3‐87

Case report: Low‐grade primary central nervous system lymphoma suspected by biopsy

Shuhei Kubota; Shinichi Okonogi; Chie Matsuura; Yasuhiro Node; Shunpei Ando; Kazuhiro Masuda; Kousuke Kondo; Naoyuki Harada; Nobuo Sugo

The Department of Neurosurgery, University of Toho, Tokyo, Japan

Low‐grade PCNSL is a rare tumor (account for 3 to 4% of the total PCNSL) and the treatment is still not established. Here we report a 46 years old gentleman presented with sudden hemiparesis of right upper and lower limbs. Brain MRI revealed a legion located on left parietal lobe, with high intensity on T2WI with perifocal swelling and enhancement. Biopsy was performed. Pathological sample from the biopsy revealed proliferation of small atypical cells with CD3, CD20 positive and MIB‐1 20% positive. Bodian and LFB stain showed a small proportion of demyelination. From the pathological finding low grade PCNSL was suspected, so we have done a steroid pulse therapy and maintenance therapy. Repeated MRI after the therapy showed a reduction of tumor and improvement of the swelling. Right hemiparesis also improved. Today, the patient is continuing rehabilitation at outpatient. It is reported that PCNSL occasionally progresses resisting to steroid (Suzuki, 2009). Therefore, MR imaging follow up is considered as important.

P3‐88

Intracranial methotrexate‐associated lymphoproliferative disorder in a rheumatoid arthritis patient treated with methotrexate: a case report

Ryosuke Matsuda¹; Shizuka Miyaza²; Mitsutoshi Nakamura¹; Kentaro Tamura¹; Shuichi Yamada¹; Fumihiko Nishimura¹; Ichiro Nakagawa¹; Yasushi Motoyama¹; Young‐Su Park¹; Hiroyuki Nakase¹

¹Department of Neurosurgery, Nara medical university, Nara, Japan; ²Department of Neurosurgery, Osaka police hospital, Osaka, Japan

Background: Methotrexate (MTX) is one of the most common drug for rheumatoid arthritis (RA). However, some studies have shown that methotrexate induced lymphoproliferative disorders in the patients treated with methotrexate for a long term, namely methotrexate‐associated lymphoproliferative disorders (MTX‐LPD). We describe a rare case of MTX‐LPD with intracranial lesion under MTX therapy for RA.

Case presentation: A patient is 68‐year‐old female. A diagnosis of RA had been made 15 years before and she has received MTX therapy for 5 years. She experienced progressing palsy of right limbs and magnetic resonance imaging of brain showed a ring enhancing lesion in the left parietal lobe. Operation Open biopsy was performed for making a definite diagnosis and planning treatment. HE stain showed perivascular cuffing of a lymphoma with tumor cell infiltration. Immunohistochemistry showed a positive reaction to CD20 and lesion was demonstrated strong nuclear signal by in situ hybridization for Epstein Barr early region. Finally we made a diagnosis of MTX‐LPD. We discontinued MTX and treated with steroid. The intracranial lesion has been decreased in size and right palsy was resolved two years after the discontinuation of MTX.

Conclusions: An intracranial MTX‐LPD is extremely rare. The authors describe their particular case and review the literature pertaining to MTX‐LPD.

P3‐89

A case of primary central nervous system lymphomatoid granulomatosis ameliorated completely after treatment of corticosteroids

Takayuki Nakao¹; Shuichi Izumoto²; Naohiro Tuyuguchi¹; Amami Kato¹; Hiddeaki Yokoo³; Eisuke Enoki⁴

¹Department of Neurosurgery Kindai University School of Medicine; ²Kindai University Nara Hospital; ³Department of pathology Gunma University School of Medicine; ⁴Department of Pathology Kindai University School of Medicine

Backgruound: Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive lymphoreticular proliferation which usually involves the lugs, but may also involve the central nervous system (CNS). But, unique primary LYG of the CNS has been reported rarely. We report our experience of primary CNS‐LYG with good prognosis with corticosteroid treatment.

Patients and Methods: A 37‐year‐old female presented with headache and left leg weakness. There was no evidence of systemic disease. Her MRI of brain showed multiple small enhancing nodules in her right hemisphere with diffuse high intensity lesion on T2/ FLIR image.

Results: Brain biopsy showed atypical lymphohistiocytic cells with CD3+ and CD20+ infiltrate around the vessels. EBER‐ISH was negative. Thus primary CNS‐LYG was diagnosed. Systemic high dose corticosteroid therapy following oral corticosteroid was performed and complete remission was achieved

Conclusions: Primary CNS‐LYG is a rare disease that seems not to be associated with EBV and appears to have a better prognosis than systemic LYG with CNS localization which is frequently EBV positive.

P3‐90

Autopsy case report of intravascular large B‐cell lymphoma with nephrotic syndrome

Ayako Yamazaki¹; Toru Sakairi²; Hayato Ikota³; Hideaki Yokoo³

¹Clinical Department of Pathology, Gunma university Hospital, Gunma, Japan; ²Department of Nephrology and Rheumatology, Gunma university Hospital, Gunma, Japan; ³Department of Human Pathology, Gunma University Graduate School of Medicine, Gunma, Japan

A 74‐year‐old man with nephrotic syndrome was admitted to previous hospital due to systemic edema after 3 years of complete remission (CR). He had been treated with cyclosporine A (CyA) and prednisolone. In this hospitalization, Steroid intensive therapy was started. After a month, he developed psychological symptoms such as delusions of persecution and anorexia following tremor of face and bilateral upper limbs. Since he was suspected as steroid‐induced psychiatric disorder, he transferred to our hospital. His symptoms were rapidly deteriorated. His laboratory findings revealed elevated transaminase of liver, dysfunction of kidney and dehydration. MRI revealed fresh multiple infarction in bilateral cerebrum and cerebellum. Soon, he suffered from shock and died despite rehydration and administration of antibiotics. In autopsy, multiple infarction was found in bilateral cerebrum and cerebellum especially cingulate gyrus with plugging of vessels by atypical cells. The atypical cells were also found in other organs (lung, pericardium, prostate, kidney). Immunohistochemistry showed that these atypical cells were lymphoid origin and B‐cell in type, staining positively with CD20, CD79α, BCL6, and MUM1. A diagnosis of intravascular large B‐cell lymphoma (IVLBCL) was made. Since this patient had history of treatment of immunosuppressive agents (CyA and steroid), ‘other iatrogenic immunodeficiency‐associated lymphoproliferative disorders (oii‐LPD)’ might be in consideration.

P3‐91

A case of probably CNS infiltration developing in a patient with IgM MGUS

Hisaharu Gotou; Hirokazu Sadahiro; Sadahiro Nomura; Michiyasu Suzuki

Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

Immunoglobulin(Ig) M monoclonal gammopathy of undetermined significance (MGUS) is characterized as a serum IgM monoclonal protein < 3 g/dL, bone marrow lymphoplasmacytic infiltration < 10%, and no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity, but sometimes develops plasma cell myeloma, Waldenstrom's macroglobulinemia (WM), or non‐Hodgkin lymphoma. We present a patient with suspected central nerve system (CNS) infiltration of IgM MGUS. A 63 year‐old male with IgMκ monoclonal gammopathy of undetermined significance (MGUS) diagnosed 5 years ago, had an onset of brain tumors causing consciousness disorder and right‐sided hemiparesis in the basal ganglia, midbrain, temporal lobe, and frontal lobe. Needle biopsy disclosed diffuse large B‐cell lymphoma. These tumors was uncontrollable after standard chemotherapy of high‐dose MTX and whole brain radiation, and the patient was dead 2 months after diagnosis of CNS lymphoma. Immunohistochemistry revealed positive CD20, bcl‐2, IgM, and c‐myc, and negative CD 3 and CD138, suggesting of highly malignant lymphoma. Few report of IgM MGUS developing DLBCL with CNS infiltration have been described before. Previous reports showed lymphoplasmacytic lymphoma/WL of associated disease of IgM MGUS sometimes occurs CNS infiltration and the case of DLBCL developed from WM/LPL cells by histological transformation as a result of clonal evolution. This patient probably CNS infiltration developing in a patient with IgM MGUS.

P3‐92

A case of subdural mass lesion with chronic myeloid leukemia

Yoshihiro Kushihara¹; Ryohei Otani¹; Mayuko Inazuka¹; Ryoji Yamada¹; Takuma Kumagai^1,2; Takashi Toya²; Nobuaki Funada³; Nobusada Shinoura¹

¹Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ²Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ³Department of Hematology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

This case was a wide‐spreading subdural mass lesion that we could not diagnose. Patient was a 64‐year‐old woman with chronic myeloid leukemia, which was treated by Dasatinib and was in complete remission since two years ago. She complained swelling of cervical, axillary and inguinal lymph node since 10 days before hospitalization. We performed lymph node biopsy suspecting Malignant lymphoma, but we could not observe any specific findings except for proliferation of various cells. We stopped Dasatinib and replaced it with prednisolone(10mg/day) 4 days before hospitalization because of increasing pleural effusion. She was hospitalized for rapidly progressing occipital headache, and CT scan showed subdural mass lesion widely spreading on left hemisphere. MRI showed homogeneously contrasted subdural mass lesion without mass effect and with low intensity on DWI. Dural metastases of malignant lymphoma, chronic myeloid leukemia, subdural abscess or subdural hematoma were suspected, and we performed open biopsy. Intraoperative findings were dark‐red colored elastic tissue involving dura matter without infiltration of arachnoid. Pathological findings showed diffuse infiltration of lymphocytic or plasmacytic mononuclear cells in the fibrous tissue. Histiocytic cells with rich cytoplasm were also observed. At least, no tumor cell was observed. Some kind of inflammatory disease was suspected, but we could not determine diagnosis. We would like to ask for the clinical pathology review meeting.

P3‐93

A case of progressive multifocal leukoencephalopathy with severe inflammation which differential diagnosis with brain tumor is difficult

Shinjiro Fukami¹; Jiro Akimoto¹; Tomohiro Suda¹; Yukiko Hara²; Toshitaka Nahao²; Michihiro Kohno¹

¹The Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan; ²The Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan

Introduction: progressive multifocal leukoencephalopathy (PML) is rare disease which present in the white matter of immunocompromised patients. We report a case of PML which differential diagnosis with brain tumor is difficult.

Case description: 72‐yerd‐old woman with long‐term steroid for dermatomyositis presented dysarthria and memory disturbance. Brain MRI demonstrated slightly high signal of DWI, high signal of FLAIR, and punctate pattern of enhanced image in the white matter of bilateral frontal. The diagnosis from radiological image was difficult. We resected one gyrus of right frontal lobe for pathological diagnosis.

Pathologic finding: Many inflammatory cells such as lymphocytes, plasma cells, and macrophage were detected mainly on perivascular of the white matter. According to the lymphocytes, there were more CD3 positive cells than CD20 positive cells, and the large lymphocytes were also detected. In the background, many cells which had oval swelling nucleus were distributed. Although the initial tentative diagnosis was T cell malignant lymphoma, many cell with swelling nucleus were positive to JC virus capsid protein VP1 and minor capsid protein VP2/3 indicating they were JC virus infected cells. The final diagnosis was PML with severe inflammation.

Clinical course: Initially she was treated by high doze methotrexate therapy because of initial diagnosis T cell lymphoma. Neurological image and clinical symptom were improved after initial treatment. After diagnosis of PML, She was treated by anti‐JC virus medicine, and neuroradiological image and clinical symptom was improved further.

Conclusion: PML with severe inflammation has difficulty with diagnosis of malignant lymphoma in radiological and pathological.

P3‐94

A case of giant mature teratoma in third ventricle

Masataka Mikai; Chie Matuura; Yutaka Huchinoue; Yasuhiro Node; Shinichi Okonogi; Shunpei Ando; Hiroyuki Masuda; Kousuke Kondo; Naoyuki Harada; Nobuo Sugo

Department of Neurosurgery (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan

Intracranial teratoma occur frequently in children and young people and is rare about 0.4% in brain tumors. We report a case of the giant mature teratoma in third ventricle. A 5‐years old male had presented with a tremor two years before. He pointed out a large tumor of third ventricle and hydrocephalus on Computed Tomography(CT). The tumor size was 56mm×48mm. It was well‐demarcated with the surrounding brain and it contained calcification. The tumor indicated a high signal partly on T1WI and T2WI of magnetic resonance imaging(MRI). We thought preoperative diagnosis was a teratoma. First of all, we biopsied the tumor and detained Ommaya reservoir using neuroendoscopy. The biopsy results were fat‐like tissue and fibroblasts. Next, we removed totally through interhemispheric transcallosal transchoroidal approach. The tumor included fat tissue, hair tissue, calcification like tooth. It was adhered strongly to the near of the pineal gland. Pathologically, the diagnosis was mature teratoma. After the operation, the tremor was disappeared, and he was discharged from the hospital without neurological deficit. For diagnosis of teratoma, a combination of the images and pathology is very important.

P3‐95

Supratentorial purely cortical anaplastic ependymoma ‐A case report‐

Jun Nishiyama¹; Fumiya Sano^1,2; Naokazu Hayashi¹; Yoichi Nonaka¹; Chie Inomoto²; Naoya Nakamura²; Takatoshi Sorimachi¹; Han Soo Chang¹; Mitsunori Matsumae¹

¹The Department of Neurosurgery, Tokai University School of Medicine, Kanagawa, Japan; ²The Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan

Introduction: Ependymomas that occur in the brain surface are rare. Purely cortical anaplastic ependymoma has examined past literature but few reports. Since we experienced a case that considered as supratentorial purely cortical anaplastic ependymoma this time, we will report a case and review of the literature.

Case: A 16‐year‐old man. He has no special medical history nor family history. Because he was aware of headaches, left facial paralysis, numbness of the left hand, he consulted his previous doctor. Intracranial hemorrhage was suspected by the head computed tomography. The head MRI of our hospital confirmed a contrast lesion of 5 cm large in contact with the dura of the right frontal lobe. Differential diagnosis considered meningioma, solitary fibrotic tumor, etc., but none of the typical findings were found. Intraoperative findings did not adhere to the dura mater, and the boundary with the brain was completely removed except adhesion of the tumor except for the bottom of the tumor. The pathological diagnosis was anaplastic ependymoma. After surgery, radiation therapy is done, there is no recurrence.

Discussion: Typical rosette structure was not apparent, but the present case was approved RELA fusion. From the viewpoint of recognizing a branched capillary network with clear cell as the background, he possibility of supratentorial clear cell ependymoma with branching capillaries was also thought. The age at onset, under 18 years of age, also considered a possibility that the prognosis is relatively good.

Conclusion: Differential diagnosis with supratentrial tumor needs to keep this disease in mind.

P3‐96

Juvenile xanthogranuloma mimicking brain stem tumor in an infant: A case report and a review of literatures

Yoshinori Kodama¹; Takumi Yamanaka²; Naoya Hashimoto²; Eiichi Konishi³; Kyoko Itoh¹

¹Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan; ²Department of Neurosurgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; ³Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Introduction: Juvenile xanthogranuloma (JXG) is an uncommon disorder of histiocytic cell proliferation. It typically arises from cutaneous tissue usually occurring in childhood. The lesion in the central nervous system (CNS) is rare. An operated case of the solitary CNS‐JXG is reported with a thorough review of English literatures.

Clinical summary: An eight‐month male infant was admitted because of the left hemiplegia. Brain MRI showed a tumor localizing in the brain stem. Low grade glioma, such as pilocytic astrocytoma or pontine glioma, was suspected. Tumor resection was performed. Histopathological examination indicated the diagnosis of JXG as described in detail below. There were no skin lesions. Bone XP, chest CT and abdomen CT showed no lesions in other visceral organs. Therefore, we concluded it as a brain‐localized single lesion.

Pathological findings: Histopathological examination revealed diffuse proliferation of histiocytes and fibroblastic cells, admixed with lymphocytes, foamy macrophages and a small number of multinucleated giant cells. There was no necrosis. Immunohistochemical studies demonstrated most of the cells being positive for CD68, factor XIIIa and negative for CD1a, GFAP, neurofilament, BRAF(V600E). S‐100 immunostaining was equivocal. Histopathological findings and immunostaining pattern of this lesion were consistent with JXG.

Conclusion: We reported a case of solitary CNS‐JXG with histological and immunohistochemical examinations.

P3‐97

Germinoma recurrence outside the previous radiation field 15 years after complete remission

Tomoo Matsutani¹; Hisayuki Murai²; Yue Gao¹; Yasuo Iwadate¹

¹Department of Neurological Surgery, Chiba University Graduate School of Medicine; ²Chiba‐ken Saiseikai Narashino Hospital

Germionma is curable disease presenting 90% survival at 10‐years, due to appropriate radiation and chemotherapy. However, SEER database suggested thet germinoma might recur a few decades later. The germinoma petient, who present recurrence 15 years after the initial treatment, is reported.

A 36 year‐old woman has a history of neurohypophysial germionma, which was thought to be completely cured after 30Gy of extended local irradiation with 10Gy local boost and chemothrapy, including cisplatin and etoposide. 15 years later, she presented cerebral tumor outside the radiation field, and it was pathologically diagnosed as germinoma recurrence. Carboplatin and etoposide were administrated, and tumor completely disappered. However, tumor recurred 9 months after the treatment, and sterotactic radiosurgery folllowed by additional chemothrapy, including ifosfamide, cispatin and etoposide, could achieve complete remission, again.

Several reports suggested germinoma could recur long time after the initial treatment. In our case, tumor recurred at extra‐radiation field, which means that some tumor could not be cured by only chemothrapy without irradiation, even if it showed long‐term remission. For better quality of life in the long‐time surviving germinoma petients, lowering the dose of radiation with intensive chemothrapy is required, but to asses the survival results, long follow‐up, more than 15 years, is essential.

P3‐98

A case of medulloepithelioma in the posterior cranial fossa

Akihiro Inoue¹; Shohei Kohno²; Kosuke Kusakabe³; Kyoko Moritani⁴; Riko Kitazawa⁵; Junko Hirato⁶; Satoshi Suehiro¹; Shirabe Matsumoto¹; Hideaki Watanabe¹; Takeharu Kunieda¹

¹Department of Neurosurgery, Ehime University School of Medicine, Ehime, Japan; ²Department of Neurosurgery, Japanese Red Cross Society Himeji Hospital, Hyogo, Japan; ³Department of Neurosurgery, Ehime Prefectural Central Hospital, Ehime, Japan; ⁴Department of Pediatrics, Ehime University School of Medicine, Ehime, Japan; ⁵Division of Diagnostic Pathology, Ehime University Hospital, Ehime, Japan; ⁶Department of Pathology, Gunma University Hospital, Gunma, Japan

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors has been revised, in which genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both, morphological and genetic analyses based on this classification. A 10‐month‐old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumours. The patient was immediately treated with systemic high dose chemotherapy. Follow‐up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine hematoxylin and eosin staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis.

P3‐99

Primary intracranial peripheral PNET case report

Wendong Lyu¹; Keisuke Moriya¹; Kentaro Chiba¹; Takashi Komori²; Yasuo Aihara¹; Toshihisa Tsuruta³; Takakazu Kawamata¹

¹Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ²Medical Inspection Department, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ³Pediatrics, Tokyo Women's Medical Universituy, Tokyo, Japan

In 2016 CNS WHO classification, the term CNS PNET that termed in 2007 was removed from the diagnostic lexicon. Time before 2007, these tumor were termed supratentorial PNET. On the other hand, the peripheral PNET (pPNET) is originating from soft tissue and bone like Ewing's Sarcoma. These two types have similar histological appearance but different prognosis.9‐year‐old girl had suffered from vomiting without nausea. CT scan revealed a right fronto temporal cystic tumor. MRI shows an irregular contrast enhancement. An urgent craniotomy with complete removal of the lesion was perfomed. The tumor was located above the pia mater with a dural implantation. The frozen section diagnosis was of small round cell tumor. On the basis of this diagnosis the patient was planned to undergo CSI (craniospinal irradiation) after the chemotherapy following the protocol of the medulloblastoma. After the first chemotherapy, the FISH was performed and EWSR1 gene‐related rearrangement was detected. Then we diagnosed the tumor as pPNET and changed the radiation therapy from CSI to local radiation therapy. CNS PNET and pPNET have similar histological appearance but have different originating and immunohistochemical results. We report one case of intracranial pPNET. The occurrence of pPNET at this site is unusual. Immunophenotypical as well as genetic analysis play a key role in the diagnosis and the distinction from CNS PNET.

P3‐100

Recurrence of biphenotypic sinonasal sarcoma with cerebral hemorrhaging: A case report with an 11‐year follow‐up

Hirotaka Fudaba¹; Yasutomo Momii¹; Kouhei Onishi¹; Takashi Hirano²; Hidetaka Yamamoto³; Minoru Fujiki¹

¹Department of Neurosurgery, Oita University Faculty of Medicine, Oita, Japan; ²Department of Otolaryngology, Oita University Faculty of Medicine, Oita, Japan; ³Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan

Biphenotypic sinonasal sarcoma (BSNS) is a newly classified tumor that is characterized by neural and myogenic differentiation. We herein report a rare case of the recurrence of BSNS with intracranial hemorrhaging and a review of the literature. A 70‐year‐old man presented with disturbance of consciousness and vomiting blood. He had undergone resection of a sinonasal tumor 11 years earlier and shown no recurrence at his last follow‐up 4 years ago. Computed tomography showed cerebral hemorrhaging around a low‐density mass that occupied the left frontal base and left ethmoid sinus. Total resection was performed. A histological examination of tumor specimens obtained from the first and the second resections revealed almost the same characteristic morphological features and the patient was diagnosed with BSNS. The lesion was negative for any fusion genes, such as PAX3‐MAML3, PAX3‐FOXO1 or PAX‐NCOA1 fusion. The long‐term progression of BSNS is not clear. This case appears to be the first reported recurrence of BSNS with cerebral hemorrhaging. BSNS should be considered to need long‐term follow‐up.

P3‐101

Preservation of staining property STAT6 immunostaining in solitary fibrous tumor/haemangiopericytoma with preoperative embolization

Hadzki Matsuda¹; Takeo Uzuka¹; Fumi Higuchi¹; Hirohisa Yajima¹; Mihoko Ishikawa³; Phyo Kim¹; Keisuke Ueki^1,2

¹Department of Neurologic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan; ²Comprehensive Cancer Center, Dokkyo Medical University Hospital, Mibu, Tochigi, Japan; ³Department of Pathology, Dokkyo Medical University Hospital, Mibu, Tochigi, Japan

We examined conditions adequate immunoreactivity of STAT6, using a specimen of solitary fibrous tumor/haemangiopericytoma (SFT/HPC) which underwent preoperative embolization.

Patient: A 26 y.o. man who had solid, irregularly shaped and well‐enhanced extraaxial tumor. Angiography and tumor embolization were perfomed followed by the resection at the same day. Intraoperative diagnosis was the SFT/HPC. Warm ischemic time from the start of embolization to complete tumor excision and immersion in 10% neutral buffered formalin was about 17hrs.

Samples: The tumor specimen were cut into about 5*10mm size and formarin‐fixed as follows: 15hrs, 39hrs (also prepared the specimens for routine path‐diagnosis), 63hrs, 87hrs, 7days, 15days, 22days. [Antibody] polyclonal anti‐STAT6(S‐20): sc‐621, 1:50, Santa Cruz, Dallas, TX

Results: The STAT6's nuclear positivity were more distinct with short‐time‐fixed samples, but contained the area that were kept relatively good even for specimens of the longest 22‐days‐fixed. On the other hand, in the specimen of the largest diameter of tumor prepared for routine path‐exam, adequate immunopositivity were at the only within 500 mcm of the tumor surface or within 100 mcm around the relatively large blood vessel branch within the tumor. Immunoreactivity remarkably weakened inside the tumor in which formalin permeation was delayed.

Conclusion: The time‐lag from the ischemia to the formalin penetration, which affected the immunoreactivity of STAT6, was remarkable attenuation even within a relatively short period of time within 40 hours after immersion in the formalin. It might be improved by dividing the tumor before the immersion in formalin for tumors larger than 1 cm in diameter.

P3‐102

δ‐catenin modulates bevacizumab‐induced glioma invasion

Toshihiko Shimizu; Kazuhiko Kurozumi; Joji Ishida; Yoshihiro Otani; Yusuke Tomita; Yasuhiko Hattori; Atsuhito Uneda; Yuji Matsumoto; Tomotsugu Ichikawa; Isao Date

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Introduction: While bevacizumab suppresses angiogenesis, it has also been reported to cause invasive proliferation. We evaluated the effects of bevacizumab on the invasiveness of glioma cells and determined target genes involving in the regulation of bevacizumab‐induced invasion.

Material and Methods: Human glioma U87δEGFR cells were stereotactically injected into the brains of mice. Bevacizumab was administered intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology observations and mRNA was extracted from the orthotopic U87δEGFR glioma cells. Gene expression was assessed by qRT‐ PCR arrays, which included factors such as adhesion molecules. Expression of genes‐of‐interest was compared between the bevacizumab and control groups. The cytotoxicity of bevacizumab and its effect on U87δEGFR, U251MG, A172, Gli36 and its invasiveness were investigated. Expression of key factors was targeted by siRNA, and shRNA knockdown, and cell invasiveness was analyzed.

Results: In vivo, bevacizumab treatment increased glioma cell invasion. qRT‐PCR array analysis revealed upregulation of δ‐catenin (CTNND2) and several other factors. Down regulation of δ‐catenin by shRNA decreased bevacizumab‐induced glioma invasion. In vitro experiments showed that a low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased. And δ‐catenin was upregulated by a low dose of bevacizumab treatment. Silencing of δ‐catenin decreased the bevacizumab‐induced glioma invasion.

Conclusion: This study showed that some ECM factors were changed, and glioma cell invasion was induced during bevacizumab therapy. The findings suggest that δ‐catenin regulates bevacizumab‐induced glioma cell invasion, and may be a novel target for glioma treatment.

P3‐103

A case of radionecrosis, 2 years after radiation therapy

Kosuke Katayama¹; Kenichiro Asano¹; Kiyohide Kakuta¹; Akira Kurose²; Hiroki Ohkuma¹

¹Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan; ²Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Aomori, Japan

Introduction: Here we report a case of radionecrosis developed 2 years after temozolomide concomitant radiation therapy for anaplastic astrocytoma.

Case: A 60 years old men was diagnosed as right frontal brain tumor, and admitted in our hospital in August 20XX. The first surgery was performed. The diagnosed was anaplastic astrocytoma (WHO2007). After the surgery, Stupp's regimen was performed. In March 20XX+1, the tumor recurred and the second surgery was performed. Placement of BCNU wafer was performed, too. The diagnosis was anaplastic astrocytoma, IDH‐mutant (WHO2016). Maintenance therapy was continued, however, the tumor recurred in January 20XX+3. The third surgery was performed in February.

Histological findings: Extensive geographical coagulative necrosis was found below resected lumen. In brain tissue around the lesion, astrocytosis and invasion of lymphocytes and histiocytes were observed. No tumor cell was found under the BCNU wafer. Hyaline degeneration was remarkably observed in a part of vessels. Coagulation necrosis of vessels was also observed frequently. We diagnosed this case as radionecrosis, however, IDH mutated cells existed partially.

Discussion: Radionecrosis is reported to occurs within six to fifteen months after the radiotherapy, which mimics recurrence of metastatic brain tumor or malignant glioma. We experienced a case of radionecrosis developed 2years after the radiotherapy, and thought it unlikely to be the radionecrosis. Here we report the pathological findings, clinical course and radiographical findings of this case with consideration from literatures.

P3‐104

A case of primary intracranial rhabdomyosarcoma

Maki Sakaguchi^1,2; Masashi Kinoshita¹; Katsuyoshi Miyashita¹; Shingo Tanaka¹; Hiroko Ikeda²; Takayuki Nojima²; Mitsutoshi Nakada¹

¹Department of Neurosurgery, Kanazawa University Hospital, Kanazawa, Japan; ²Department of Diagnostic Pathology, Kanazawa University, Kanazawa, Japan

Primary intracranial rhabdomyosarcoma is a very rare tumor that poses great diagnostic challenges to pathologists. We report a case of a 10‐year old female who presented with symptoms of increased intra‐cranial pressure, dressing apraxia and upper extremity paralysis secondary to recurrent hematoma formation in the left occipital area. A neoplasm was identified after the second hematoma evacuation and the primary pathologic consideration at that time was primitive neuroectodermal tumor. Initially, chemotherapy and radiotherapy were given, however, therapy subsequently shifted to more powerful chemotherapeutic agent with the confirmed diagnosis of rhabdomyosarcoma. Therapy response was noted and lasted for few years until development of recurrence. The patient had survived for 53 months from initiation of therapy. Histologically, the tumor consisted of diffuse proliferation of immature spindle cells with marked cytologic atypia and eosinophilic cytoplasm, arranged in fascicular and storiform pattern. There are frequent mitoses and scattered multi‐nucleated giant cells with eosinophilic cytoplasm. Immunohistochemically, the tumor cells show expression of skeletal muscle differentiation (myogenin, desmin, HHF35) and INI1 expression was retained. To the best of our knowledge, there are only 50 cases of primary intracranial rhabdomyosarcoma published. It is important to include rhabdomyosarcoma as a differential diagnosis when dealing a poorly differentiated tumor in the central nervous system. In this case, an accurate diagnosis of primary intra‐cranial rhabdomyosarcoma contributed to appropriate treatment and long‐term survival of a patient.

P3‐105

A case of mucinous carcinoma considered malignant transformation from intracranial germ cell tumor

Yoji Yamaguchi¹; Takashi Sasayama²; Hiroto Kajimoto²; Akiho Yamamoto³; Maki Kanzawa³; Takanori Hirose⁴; Tomoo Ito³; Eiji Kohmura²

¹Department of Neurosurgery Yodogawa Christian Hospital; ²Department of Neurosurgery Kobe University; ³Department of Diagnostic Pathology Kobe University; ⁴Department of Pathology for Regional Communication Hyogo Cancer Center

Introduction: To our best knowledge, there is no report of primary intracranial mucinous carcinoma so far.

Case: A four‐year‐old male child underwent a partial removal of a pineal tumor. Pathological diagnosis was mixed germ cell tumor including mature teratoma and choriocarcinoma. After the surgery, he received radiation therapy (whole brain and local), followed by chemotherapy up to 6 years old. Over 20 years has passed without tumor progression. However, the residual tumor growth and a hydrocephalus was recognized at the age of 27. He underwent an endoscopic third ventriculostomy (ETV) and a partial tumor removal. Pathologically, layered keratinized material with monocyte infiltration was found, however, there was no malignancy. The tumor progression was recognized about a half year later. Therefore, we diagnosed growing teratoma syndrome and performed CARE chemotherapy (carboplatin and etoposide) twice and a subtotal tumor removal. Pathological examination revealed glandular epithelium containing goblet cells with a lot of mucus. We diagnosed mucinous carcinoma.

Conclusion: If a residual tumor of germ cell tumor grows rapidly, a tumor removal should be necessary to diagnose pathologically.

P3‐106

A case of front‐temporal suprasellar papillary glioneuronal tumor

Akira Tamase¹; Osamu Tachibana¹; Sho Takata¹; Satoko Nakada²; Sohsuke Yamada²; Hideaki Iizuka¹

¹Department of Neurosurgery, Kanazawa Medical University, Uchinada, Japan; ²Department of Clinical Pathology, Kanazawa Medical University, Uchinada, Japan

Papillary glioneuronal tumors are rare tumor type, which were only recently recognized and histologically characterized by their pseudopapillary architecture associated with compact areas composed of neuronal elements in different maturation states. The authors present 16‐year‐old woman with papillary glioneuronal tumor. She was admitted to our institute because of her visual disturbance. Imaging showed a demarcated, mainly solid and cystic calcified frontal base to suprasellar extending tumor. The patient underwent surgery with bifrontal craniotomy. Histologically, it was observed pseudo‐papillary growth of GFAP positive cells and synaptophysin‐positive interpapillary collections of neurocytes. The cell nuclear fissions were not noticeable and Ki‐67 was 4.1% at the maximum site. After surgery, her visual disfunction was improved.

P3‐107

A Case of Solitary Fibrous Tumor of NAB2 Exon 6‐STAT6 Exon 17

Kodai Matsuda¹; Tsugu Hitoshi²; Tsutomu Yoshioka²; Hirata Yoko²; Kenichi Nishiyama³; Katsuyuki Hirakawa¹; Kazuki Nabeshima⁴; Touru Inoue⁵

¹Department of Neurosurgery, Fukuoka City Hospital, Fukuoka Japan; ²Department of Neurosurgery, Fukuoka Red Cross Hospital, Fukuoka Japan; ³Department of Neuropathology, Fukuoka Red Cross Hospital Fukuoka Japan; ⁴Department of Neuropathology, Faculty of Medicine, Fukuoka University Hospital, Fukuoka Japan; ⁵Department of Neurosurgery, Faculty of Medicine, Fukuoka University Hospital, Fukuoka Japan

The solitary fibrous tumor (SFT) is a relatively rare tumor among primary brain tumors. The NAB2‐STAT6 fusion gene is a driver mutation of SFT and has genetic changes similar to those of hemangiopericytoma (HPC). Recently, various NAB2‐STAT6 genotypes have been confirmed, and the relationship between genotypes and malignancy has been reported. A 49‐year‐old woman was referred to our department because of a 2‐week history of left occipital headache and nausea. Brain magnetic resonance imaging (MRI) showed a well‐demarcated and strongly enhanced mass with multi cystic compartments in the left occipital region. The mass was approximately 40 mm in diameter. A subarachnoid space was found between the tumor and the left occipital lobe, suggesting a extramedullary situated tumor. However, there was no dural tail sign. Surgical resection of the tumor was performed. The tumor was mildly elastic and hard and bleed easily. The tumor was grayish, with a clear boundary between the tumor and the brain surface. The tumor was resected sub‐totally because it had invaded into the left transverse sinus. Histological examination showed moderate cellularity with round or oval nuclei, collagenous stroma, 1 mitosis per 10 high‐power fields, and no necrotic areas. Immunohistochemical examination showed diffuse positivity for STAT 6 and CD 34. Genetic analysis showed NAB2 exon 6‐STAT6 exon 17 fusion gene. We finally diagnosed SFT.

P3‐108

Usefulness of PCR direct sequence on definitive diagnosis for chondrosarcoma: ‐two case reports‐

Taichi Shimabukuro¹; Takafumi Nishizaki¹; Makoto Ideguchi¹; Natsumi Fujii¹; Machiko Ohno¹; Norio Ikeda¹; Tokuhiro Kimura²; Eiji Ikeda²

¹The Department of Neurosurgery, Ube‐Kohsan Central Hospital, Yamaguchi, Japan; ²The Department of Pathology, Yamaguchi University Graduate School of Medicine

Introduction: Performing a differential diagnosis between chondrosarcoma (CS) and chordoma (CH) is sometimes difficult. Because CH has a poorer prognosis than CS, it is critical to perform an accurate diagnosis. We report two cases of CS where the PCR‐direct sequence proved to be useful in differential diagnoses. Case1; A 73‐year‐old woman with bilateral abducens paralyses onset. Imaging showed the heterogeneously enhanced mass lesion on MRI with destruction of clivus bones. Tumor resection under endoscope was performed by endonasal approach.

Pathological findings: Polygonal cells proliferated with reticular, funicular and solitary pattern formation in myxomas‐like extracellular matrix. Immunohistochemical staitin (IHC) showed positive for S100, but negative for AE1/AE3, CAM5.2, and EMA. The MIB1‐LI was 1%. IDH1‐R132G mutation was detected by PCR‐direct sequence, while IDH2‐R172 was wild type. Case2; A 33‐year‐old man with right trigeminal neuralgia onset. Imaging showed the ring‐like enhanced tumor bulk located in right cavernous sinus to cerebellopontine angle. Tumor resection was performed by right suboccipital craniotomy.

Pathological findings: While chondroid tissue was mainly seen, the tumor cells with palisading arrangement in myxoid stroma were partially visible. IHC was negative for AE1/AE3, CAM5.2, and EMA. The MIB1‐LI was 2%. IDH1‐R132G mutation was detected in PCR‐direct sequence, while IDH2‐R172 was wild type.

Discussion and conclusions: The IDH1 mutation was found to be common in CS and rarely so in CH, although the imaging and the pathological findings of both tumors were very similar. We conclude that PCR‐direct sequence is useful in differential diagnosis between CS and CH.

P3‐109

A Case of intraventricular giant cell glioblastoma

Tomoko Omura¹; Katsuya Umeoka¹; Toshimasa Yamada¹; Koji Adachi²; Takayuki Mizunami¹; Tsutom Hatori³; Akio Morita⁴

¹Departement of Neurosurgery, Chiba Hokuso Hospital Nippon Medical School, Chiba, Japan; ²Departement of Neurosurgery, Musashi Kosugi Hospital Nippon Medical School, Kanagawa, Japan; ³Departement of Pathology, Chiba Hokuso Hospital, Nippon Medical School, Chiba, Japan; ⁴Departement of Neurosurgery, Nippon Medical School, Tokyo, Japan

Giant cell glioblastoma (GCG) is a rare histological variant of glioblastoma(GBM). We report a case of a 60‐year‐old man who presented short‐term memory impairment. Magnetic resonance imaging(MRI) showed a well‐circumscribed mass approximately 6 cm in size, which was located within the inferior horn of the right lateral ventricle. He presented progressive left‐sided hemiparesis and impaired consciousness after admission. The patient underwent surgical removal through transcortical route 15 days after admission. Grossly, the tumor was seen as hypervascular mass with very hard consistency. Histological examination revealed pleomorphic nuclei and necrosis. Most striking feature was numerous bizarre multinucleated cells. Staining for IDH‐1 R132H, GFAP, EMA, vimentin, and S‐100 were negative in the tumor cells. Staining for p53 was positive. MGMT promoter hypermethylation and 1p/19q co‐deletion were not detected. The final pathological diagnosis was GCG. The patient underwent radiotherapy and temozolomide chemotherapy. However, MRI showed cerebellar new lesion during adjuvant therapy, which we highly suspected to be a dissemination. We performed whole brain radiotherapy and added bevacizumab. After adjuvant radiochemotherapy, a follow up MRI demonstrated decrease of enhanced lesions. Because intraventricular GCG is extremely rare, we also reviewed pertinent literature regarding this case.

P3‐110

A case of pontine glioma occurring 14 years after chemoradiotherapy of NGGCT

Takayuki Yasuda^1,2; Yoshiki Arakawa¹; Katsutsugu Umeda³; Satsuki Asai⁴; Yosuke Yamada⁴; Masahiro Tanji¹; Yohei Mineharu¹; Soichi Adachi³; Susumu Miyamoto¹

¹Department of Neurosurgery, University of Kyoto, Kyoto, Japan; ²Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ³Department of Pediatrics, University of Kyoto, Kyoto, Japan; ⁴Department of Diagnostic Pathology, University of Kyoto, Kyoto, Japan

We report a rare case of pontine glioma that occurred 14 years after chemoradiotherapy of nongerminomatous germ cell tumors (NGGCT). An 8‐year‐old girl presented with rapid reduction of visual acuity with high level of serum AFP and b‐HCG. As she had suprasellar lesion and was diagnosed as NGGCT, she underwent radiotherapy (local 26 Gy, whole ventricle 24 Gy) and chemotherapy (CPA, CDDP, VP‐16). Although the tumor was contracted without recurrence in 14 years, T2 / FLAIR high‐intense lesion on the pons appeared at the age of 22 and gradually grew with gadolinium‐enhanced portion. As methionine PET showed high accumulation in that lesion, she underwent stereotactic biopsy. Histopathological examination showed that it was composed of small round cells with round nucleus and partial high cell density similar to oligodendroglioma‐like cells. Neither microvascular proliferation nor necrosis was found. Immunohistochemical study showed positive staining for ATRX, GFAP, and Olig2, whereas negative for IDH1 R132H, MGMT, and p53 staining. The Ki‐67 labeling index was 10%. Only 1p loss was identified using FISH analysis. Therefore, it was diagnosed as low‐grade glioma, WHO grade 2. Then she received temozolomide and her enhanced‐lesion was reduced. Pontine glioma (diffuse midline glioma in WHO 2016) occurs frequently in childhood, and morphologically consisted of astrocytic component. Radiation induced glioma is rare with a high incidence in young people, but it has been reported to be no difference in genetical alterations between radiation‐induced gliomas and spontaneously occurring gliomas. We discuss the molecular analysis of this case.

P3‐111

A case of gliofibroma in adults who underwent oncogene panel test

Shunsaku Takayanagi¹; Masashi Nomura¹; Shota Tanaka¹; Masako Ikemura²; Aya Usiku²; Sinji Kohsaka³; Hiroyuki Aburatani⁴; Hiroyuki Mano³

¹Department of Neurosurgery, University of Tokyo, Tokyo, Japan; ²Department of Pathology, University of Tokyo hospital, Tokyo, Japan; ³National Cancer Center Research Institute; ⁴Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan

Introduction: gliofibroma is a tumor with glia component and mesenchymal component, and it is a very rare tumor that has only been reported to date by about 40 cases. It occurs mainly in children and is often a benign tumor. We report a case of adult patient with gliofibroma who had recurrence early postoperatively and underwent oncogene panel examination (Todai Onco Panel, TOP).

Case: A 40‐year‐old man who had no medical past history presented with repeated eye sticky seizures. In the head MRI, a contrast lesion with a diameter of 3 cm was recognized in the left temporooccipital region. The tumor was total removed by surgery. About 2 months after surgery, because nodules appeared in the removed cavity, we considered recurrence and the patient underwent radiotherapy.

Pathologic findings: Histologically, tumor cells with distinct chromatin‐deforming distortion and notches with a circular to spindle‐shaped nucleus were densely proliferated and accompanied by a desmoplastic response. Neurons and glia cells, which are thought to be non‐neoplastic, are intervened between islands. The nuclear fission image was not clear. Results of immunostaining were as follows. EMA (‐), LCA (‐), EG (‐), PFR (‐), SIGMA (‐), SIAP BRAF (‐), CD21 (‐), CD34 (‐). The MIB1 positive rate is about 7% in the high part. [Oncogene panel test result] Mutation of ARID1B was confirmed.

Discussion: Because gliofibroma is a rare disease, the characteristics of the disease are still unclear. The accumulation of cases and pathological and genetic analysis are necessary in the future.

P3‐112

Epithelioid hemangioendothelioma that metastasizes to the temporal lobe and cerebellum

Yasuzumi Matsui¹; Yoshiki Arakawa¹; Masahiro Tanji¹; Youhei Mineharu¹; Kazumichi Yoshida¹; Yasushi Takagi²; Susumu Miyamoto¹

¹The Department of Neurosurgery, University of Kyoto, Kyoto, Japan; ²The Department of Neurosurgery, University of Tokushima, Tokushima, Japan

Background: Epithelioid hemangioendothelioma is a non‐epithelial tumor derived from vascular endothelium discovered by Sharon Weiss et al. in 1975. Pathologically it shows the findings between angiosarcoma and hemangioma, but from genetically it shows different properties from both. Metastasis often occurs with a relatively slow course, and no effective treatment has been established. We report on a case of epithelioid hemangioendothelioma with intracranial metastasis.

Case: 20 year old male. An abnormal shadow was pointed out in the lung at the screening examination, and multiple examination showed multiple granular shadows in the lung. Since it was asymptomatic, three years passed and again an examination pointed out an abnormal shadow in the lung. Therefore, it was a close examination, in addition to multiple granular shadows in both lungs, multiple hepatic metastasis and cortical metastasis were observed. TBLB was performed, and diagnosis of Epithelioid hemangioendothelioma was obtained. It was introduced to our hospital for the purpose of treatment, and the head MRI revealed an expansion of the edematous change of the lesion.

Conclusion: Epithelioid hemangioendothelioma develops in the whole body, in particular occurs in lung, liver, bone, soft tissue, rarely occurs in the skull. This time, we discovered Epithelioid hemangioendothelioma on the left temporal lobe, and relapsed after 5 and 20 months. Sensitivity to radiation and chemotherapy is low from previous reports and surgical treatment should be selected for resectable cases.

P3‐113

A case of hemangioblastoma with disseminating recurrence

Yasuhide Makino; Yoshiki Arakawa

The Department of Neurosurgery, Kyoto University, Kyoto, Japan

Case presentation: A 41‐year‐old man presented with headache, nausea and dizziness. MRI showed a solid tumor suspecting hemangioblastoma in his left cerebellum. He underwent tumor resection and histopathological diagnosis could be hemangioblastoma but showing the similar findings of ependymoma. Three years and 11 months after the removal, MRI showed newly two lesions in his right cerebellum and a lesion in his Th2 level of thoracic spinal cord. The cerebellar lesions were removed and they were recurrent hemangioblastoma. One year later, MRI showed multiple disseminating lesions in his cerebellum and thoracic spinal cord. He received stereotactic radiotherapy in these recurrent lesions.

Discussion: Histologically, hemangioblastoma is characterized by capillary network development and stromal cell proliferation. The stromal cells have abundant cytoplasm packed with lipid vacuoles and can exhibit a clear cell‐like appearance in specimens. It has been known to be difficult to distinguish hemangioblastoma from clear cell ependymoma. The leptomeningeal dissemination of hemangioblastoma was rare. We discuss this rare case with literature consideration.

P3‐114

An elderly patient with massive dissemination diagnosed with pineal parenchymal tumor of intermediate differentiation (PPTID): An autopsy case

Kazuhiro Miyasaka¹; Ichiyou Shibahara¹; Tooru Tateoka³; Akinori Inamura¹; Masashi Akiya²; Madoka Inukai²; Makoto Saegusa²; Toshihiro Kumabe¹

¹Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; ²Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; ³Department of Neurosurgery, Yamanashi University Faculty of Medicine, Cyuo, Yamanashi, Japan

A 71‐year‐old male presented with disorientation and gait disturbance. MRI demonstrated a 13mm‐sized pineal tumor, with multiple disseminations to the lateral ventricle and the whole spinal cord. Whole‐body CT scan were negative of primary tumor. There were no definitive findings, the result of cerebrospinal fluid cytology suspected of carcinoma, thus diagnosis of brain metastases with unknown origin was made. He died of a progressive respiratory failure 3 months after the onset. The autopsy findings revealed no primary lesions in the body, and there was a 20mm‐sized tumor at the pineal body with diffuse infiltration into the surrounding brain tissue and dissemination to the ventricle wall. The tumor cells harbor high N/C ratio, a so‐called salt and pepper chromatin, and mitosis. There was also necrotic region. Immunostaining demonstrated negative AE1/AE3, and positive Synaptophysin and NCAM, thus diagnosis of PPTID was made. Pineal tumor is extremely rare accounts for below 1% of all intracranial tumors, and 21‐54% of the pineal tumor is PPTID. Furthermore, elderly PPTID patients is rare. In the present case, considering the result of cytology and old age, we diagnosed with brain metastasis with unknown origin. Due to his poor general condition, it is doubtful that we successfully provide radiation therapy, but we should have done the biopsy of pineal tumor for the early and right diagnosis. We experienced a pineal tumor with massive dissemination, which was diagnosed by an autopsy. We should keep in mind that PPTID may be the diagnosis among brain metastases of unknown origin.

P3‐115

Papillary tumor of the pineal region: Two cases report and review of the literature

Yuji Uematsu^1,2; Junya Fukai³; Kohji Fujita³; Naoyuki Nakao³

¹School of Health and Nursing Science, Wakayama Medical University, Wakayama, Japan; ²Department of Diagnostic Pathology, Wakayama Medical University Hospital, Wakayama, Japan; ³Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan

Purpose: A variety of neoplasms such as pineal parechymal cell tumors, germ cell tumors, papillary tumor of the pineal region(PTPR), and others arise in and around the pineal gland. Among them, PTPR is rare and has not been well recognized. Thus, this report describes two cases of PTPR and reviews the literature.

Methods: The first case was a 57 years‐old man who visited to examine neurolgical condition . No deficits were revealed. MRI showed a relatively high‐intensed mass on T1‐WI with homogeneous enhancement. The second case was a 68 years‐old man who was suffered from gait and memory disturbances for five months. Neurologically, cognitive decline was revealed. MRI showed a relatively low‐intensed mass with mildly heterogeneous enhancement. Both of them were totally removed through the right occipital transtentorial approach, and have not recurred for 113 and 36 months respectively.

Results: The histology both revealed the proliferation of epithelia‐like cells around the blood vessels showing papillary and solid areas. Anaplastic features such as mitosis or necrosis were only seen in the second case. The tumor cells were immunoreactive for CK, Vim., and S‐100, but not for GFAP, Olig2, EMA, NFP, SYN, and chromogranin. MIB‐1 SI was around 1.5 and 3.5% and MGMT‐immunoreactivity was moderately and highly recognized respectively. The ultrastructure of the deparffinized specimen demonstrated intermediate filaments and reminiscent junctions.

Conclusion: Rare cases of PTPR were reported and review of the literature will be discussed.

P3‐116

A case of 16 years old, right cerebellar tumor consisting of monotonous proliferating undifferentiated small cells

Takuma Oishi¹; Shouichi Deguchi²; Kouichi Mitsuya²; Nakamasa Hayashi²; Yoko Nakasu²; Takashi Sugino¹

¹Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan; ²Division of Neurosurgery, Shizuoka Cancer Center, Shizuoka, Japan

Case of A 16‐year‐old man. Right cerebellar tumor with multilocular cyst was pointed out with CT following head injury. There were no neurological deficits. Angiography didn't show tumor staining. Although PETCT had accumulation of methionine and choline, no accumulation of FDG. Undergoing craniotomy, the whole tumor was excised macroscopically. Microscopically, fragments with a maximum of 15 x 9 x 7 mm, tumor cells which had small round nucleus and eosinophilic cytoplasm with a high nuclear cytoplasm ratio, were diffuse and dense monotonous proliferating. Tumor cells lobulating by blood vessels, reactive glial cells was observed, the desmoplasia was not recognized. In the region where the spindle‐shaped cells proliferated, six mitosis appeared in one high power fields. The boundary with the brain parenchyma was clear, tumor clusters infiltrated alveolar pattern. Necrosis was not clear. Immunohistochemically, tumors showed EMA, keratin (AE1 / AE3) and desmin staining. Neurofilament Protein and NeuN stained in a small number of cells, synaptophysin weakly positive. p53 and INI1 was positive. Negative stains included GFAP, Olig 2, chromogranin A, beta‐tubulin, myogenin, IDH1. The maximal MIB 1 labeling index was 40‐50%. Glioma, medulloblastoma, AT / RT were denied. In the mesenchymal tumor, the desmoplasia was not recognized, We diagnosed of desmoplastic small round cell tumor (DSRCT). Reconfiguration of EWSR1 and WT1 was also confirmed. Up to now, there are 6 cases of intracranial DSRCT reports. Tumor cells without desmoplasia made pathological diagnosis difficult. Despite its rarity, DSRCT expands the differential diagnosis of small round cell tumors of the CNS.

P3‐117

A case of acromegaly in which a growth hormone producing pituitary adenoma recurred rapidly after administering pegvisomant

Kenichi Oyama¹; Toshio Hirohata¹; Kazuhito Yamazaki²; Shinya Miyamoto³; Katsumi Hoya³; Yasuo Ishida²; Akira Matsuno¹

¹Department of Neurosurgery / Pituitary & Endoscopic Surgery Center, Teikyo University School of Medicine, Tokyo, Japan; ²Division of Pathology, Teikyo University Chiba Medical Center, Chiba, Japan; ³Department of Neurosurgery, Teikyo University Chiba Medical Center, Chiba, Japan

Pegvisomant is a growth hormone receptor inhibitor, which suppresses serum IGF‐1 level and improves clinical symptoms of acromegaly. Here, we report a patient with acromegaly who was introduced pegvisomant in place of somatostatin receptor ligands (SRL) followed by rapid regrowth of the pituitary adenoma. The patient was a 63‐year‐old woman with treatment‐resistant diabetes mellitus, in whom acromegaly and an invasive pituitary tumor were pointed out. We performed the first trans‐sphenoidal surgery (TSS), and removed the tumor subtotally, except the tumor in the bilateral cavernous sinuses. Pathological findings showed relatively high Ki‐67 labeling index (10%). Although we had administered SRLs (octreotide and lanreotide), we had to stop them due to their side effect, flatulence. So, instead of SRLs, we introduced pegvisomant to control the disease. Two months after administering pegvisomant, a cystic tumor recurred rapidly, so the second TSS was performed. At this time, the pathological exploration showed almost same findings as that of first specimens. We restarted pegvisomant, resulting in regrowth of the tumor in seven months, and the third TSS was performed. Pathological finding showed that Ki‐67 labeling index increased from 10 % to 18 %, and p53 converted to positive. Immunostaining for somatostatin receptor showed positivity for both subtype 2 and subtype 5. As pegvisomant seemed to be related to rapid regrowth of the tumor, we stopped pegvisomant and started to use pasireotide.

P3‐118

Invasive skull base aspergillosis in a patient with lactotroph adenoma

Yuya Nishiyama¹; Mitsuhiro Hasegawa¹; Yushi Kawazoe^1,2; Seiji Yamada³; Ryota Ito⁴; Masato Abe⁵; Yuichi Hirose¹

¹Department of Neurosurgery, Fujita Health University, Toyoake, Japan; ²Department of Comprehensive Strokology, Fujita Health University, Toyoake, Japan; ³Department of Diagnostic Pathology, Fujita Health University, Toyoake, Japan; ⁴Department of Infectious Diseases, Fujita Health University, Toyoake, Japan; ⁵Department of Pathology, School of Health Sciences, Fujita Health University, Toyoake, Japan

Aspergillosis is the most common fungal infection on the skull base, and it remains a difficult disease to diagnose and treat. We recently encountered a case of invasive aspergillosis who have lactotroph adenoma controlled by cabergoline. A 47 year‐old man had presented with nasal bleeding and diagnosed lactotroph adenoma invading the sellar floor and sphenoid sinus eleven years ago. The cabergoline treatment has been shown to be effective, and ongoing. He developed headache and visual disturbance on the left side in few weeks. MRI shows new tumor mass located medial to the optic canal. Higher doses of cabergoline was ineffective, and we therefore consider surgical resection for tumor and optic canal decompression on transsphenoidally. Although visual acuity did not recover, surgical samples show branching septate hyphae in the inflammatory granulation tissue. Antifungal agent was started immediately, Aspergillus fumigatus was identified from the culture of surgical samples subsequently. There were no significant data with brood chemical values and cerebrospinal fluid examination, therefore histopathological diagnosis is imperative in this case. We report a rare case of invasive aspergillosis presenting with lactotroph adenoma with a review of the literature.

P3‐119

A case of cavernous angioma of the optic chiasma

Kiyohide Kakuta¹; Kenichirou Asano¹; Kousuke Katayama¹; Hiroki Ohkuma¹; Akira Kurose²

¹Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan; ²Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Aomori, Japan

A 59‐years‐old male presented with angioma originating from the optic chiasma manifesting as visual disturbance. Magnestic resonance imaging relealed a heterogenous signal intensity mass at optic chiasma with a low signal intensity on T2* imaging. Right front‐temporal craniotoy was performed by the pterional approach. A subpial hematoma situated at the optic chiasm lesion. The hematoma with angiomatous component was adhere to optic chiasma, but finelly resected from srrounding structure. Histological examination of the specimens confirmed that optic chiasmal lesion was carvernous angioma. Eighteen cases of cavenous angioma of opthic nerve have been discribedand some presenting with visual disturbance. Postoperatively, his left visual aquity was slightly improved. Accoding to our case and reviews, it is the best manegiment that surgical resection with preservation of opthic nerve function.

P3‐120

IgG4 related tumor‐like or hypertrophic disease mimicking skull base meninigomas

Seiichiro Eguchi¹; Go Matsuoka¹; Kenta Masui²; Tatsuo Sawada²; Noriyuki Shibata²; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University, Tokyo Japan; ²Department of Pathology 1, Tokyo Women's Medical University School of Medicine

Subjective: IgG4 related disease (IgG4‐RD) is an entity characterized by elevated serum immunoglobulin 4 and pseudo‐tumors which contain lymphoplasmacytic infiltration of IgG4‐positve plasma cells. Lymphoplasmacyte rich meningioma and Rosai‐Dorfman disease are the differential diagnoses of the intracranial lesions related with IgG4‐RD. Here we report 2 cases of intracranial lesion of IgG4‐RD mimicking skull base meningioma.

Cases: (1) A 62‐year‐old woman underwent brain MRI because of transient global amnesia. It showed a well‐enhanced lesion enlarging along petrous bone dura and tentorium. Craniotomy was performed. There were many lymphocytes and IgG4‐positive plasmacytes histologically. Serum IgG4 was high (219 mg/dL). She was diagnosed with IgG4‐RD. (2) A 63‐year‐old woman who suffered from anosmia and underwent brain MRI. A homogenously enhanced lesion which covered anterior skull base dura, anterior falx and convexity dura was detected. Pathological diagnosis of the exenterate specimen was IgG4‐RD with bases of infiltration of IgG4‐positive lymphoplasmacytes and elevated serum IgG4.

Discussions/Conclusions: Though there have been a few cases on intracranial pseudo‐tumor related with IgG4‐RD, all cases were middle‐aged patients. The site of predilection was skull base. The lesion was homogenously well enhanced with gadolinium on MRI, like an en plaque meningiomas. But no tumor cells positive for vimentin or EMA were detected in contrast to lymphoplasmacyte rich meningiomas. Diagnostic criteria have already established and high dose steroid is effective for this disorder. It is important to suspect IgG4‐RD primarily and check the serum IgG4 if there was the finding described above on brain MRI. We have to avoid unwanted surgery.

P3‐121

A case report of a mass lesion in the brain stem positive for anti‐MOG antibodies

Kentaro Fujii¹; Kazuhiko Kurozumi¹; Toshihiko Shimizu¹; Namiko Matsumoto²; Kota Sato²; Koji Abe²; Toshiyuki Takahashi³; Kimihiko Kaneko⁴; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; ²Department of Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; ³Department of Neurology, Tohoku University School of Medicine, Sendai, and National Hospital Organization Yonezawa Hospital, Yonezawa, Japan; ⁴Department of Neurology, Tohoku University School of Medicine, and National Hospital Organization Miyagi Hospital Sendai, Japan

Background: The differential diagnosis between glioma and tumefactive demyelinating lesion (TDL) can be difficult to distinguish based on magnetic resonance imaging (MRI) findings. Here, we report a case of MOG‐antibody‐associated disease, in which the patient first received a diagnosis of TDL by biopsy, and relapsed after the treatment.

Case Presentation: A healthy 22‐year‐old man was aware of weakness in his right side and presented to a local doctor. Brain MRI revealed a lesion in the left ventral side of the medulla oblongata, so he was referred to our hospital for further examination. We considered this case as brain stem glioma according to MRI and performed a biopsy. Kluver‐Barrera staining showed extensive demyelination, and we found CD68‐positive cells at the same site. Anti‐aquaporin 4 antibody in the serum and oligoclonal band in the cerebrospinal fluid (CSF) were negative. Consequently, the pathological diagnosis was TDL. The lesion shrank after administration of steroid and we continued to observe the patient. After half a year, the patient developed generalized convulsion, and MRI revealed a scattered lesion in the right frontal lobe. He was readmitted to our hospital, and we diagnosed this case as MOG‐antibody‐associated encephalitis because MOG antibody was positive in the serum and CSF. The patient's condition improved by administration of steroid.

Conclusions: We report a case of MOG‐antibody‐associated disease that was initially misdiagnosed after the first biopsy. The definition of MOG‐antibody‐associated disease is controversial, but as preferable treatment can lead to favorable outcomes, this disease should be considered as a differential diagnosis.

P3‐122

A case report of granuloma arising from peri‐third ventricle

Koji Kondo¹; Mari Kusumi^1,2; Hitoshi Yamazaki³; Hidehiro Oka^1,2

¹Department of Neurosurgery, Kitasato University Medical Center, Kitamoto, Japan; ²Department of Neurosurgery, Kitasato University, Sagamihara, Japan; ³Department of Pathology, Kitasato University Medical Center, Kitamoto, Japan

Presentation of Case: We document the case of 51 years old woman presented with a month of memory disturbance and apathy. The MRI imaging of brain revealed a homogenously enhancing lesion occupying peri‐third ventricle. On day five she got high fever and hyponatremia. Hypothalamic disturbance and hypopituitarism were suspected. We prescribed hydrocortisone. The tumor was biopsied with neuroendoscope. Dexamethasone was prescribed post‐operative days. And memory disturbance and apathy were recovered. And tumor was disappeared from the MRI imaging.

Pathology: Section of the brain tissue shows diffuse infiltration of an admixture of inflammatory cells including lymphoid cells and macrophages. A relatively small number of enlarged atypical cells are also infiltrated in the tissue.

Discussion: Prior steroid administration may obscure the histopathologic diagnosis.

P3‐123

Extremely delayed metastasis to the brain originated once completely cured cervical cancer of uterus

Akinori Inamura; Ichiyo Shibahara; Mitsuru Dan; Kazuhiro Miyasaka; Takuichiro Hide; Toshihiro Kumabe

The Department of Neurosurgery, Kitasato University, Kanagawa, Japan

Background: We experienced a rare case of a brain metastasis from cervical small cell neuroendocrine cancer (SCNEC) of uterus 13 years after the first diagnosis.

Case: 51‐year‐old female patient of disturbed consciousness was admitted. She had previous history of a surgery and adjuvant chemotherapy for cervical SCNEC 13 years before. Her annual checkup was continued for 8 years without any recurrence thus terminated 5 years before admission. Her brain MRI demonstrated a cystic tumor at the right frontal lobe which sized 6cm in diameter. An immediate surgery was done and her consciousness fully recovered. The p16 and synaptophysin immunostain were positive thus the tumor was diagnosed as a metastasis of SCNEC. CT showed no signs of uterine recurrence but an enlarged lymph node at mediastinum. The lymph node was biopsied and diagnosed as a metastasis as well. She now undergoes chemotherapy.

Discussion: SCNEC is a rare subtype of cervical cancer which accounts for 0.5‐10%. While ordinary cervical cancer rarely shows metastasis to the brain as 0.4‐2.3%, SCNEC was reported as 5 out of 15 patients had brain metastasis. The average period between the first diagnosis and metastasis to the brain was 17.2 months, however, the maximum period was reported as long as 127 months. There has not been any consensus about how long we should follow a patient.

Conclusion: We experienced a rare case of SCNEC with extremely delayed metastasis to the brain suggesting that longer period of observation is necessary. A guideline is desired for long term observation.

P3‐124

Neuropathological change after radiotherapy for HPV‐related multiphenotypic sinonasal carcinoma

Naoto Kuroda^1,2; Chikanori Inenaga²; Yuki Amano²; Hirokazu Nakatogawa²; Yoshifumi Arai³; Yoshiro Otsuki³; Tokutaro Tanaka²

¹Department of Neurosurgery, Seirei Mikatahara General Hospital, Japan; ²Department of Neurosurgery, Seirei Hamamatsu General Hospital, Japan; ³Department of Pathology, Seirei Hamamatsu General Hospital, Japan

Introduction: HPV‐related multiphenotypic sinonasal carcinoma(HMSC) is HPV‐related tumor including myoepithelial, ductal and squamous differentiation. Surgical resection with/without postoperative radiotherapy was common, however the efficacy of each treatments (surgical resection, chemotherapy and radiotherapy) were unknown. All past patients had good clinical outcome, but brain invasion wasn't reported. We treated HMSC with brain invasion by radiotherapy alone. We retrospectively discuss about effectiveness of radiotherapy from pathological findings.

Patient and method: A 69‐year‐old man with right frontal lobe intracranial hemorrhage underwent contrast MRI and it showed tumor at right frontal lobe and sinonasal tract. We performed transnasal biopsy and IMRT (40 Gy, 20 fraction). Neuroimaging study showed tumor reduction. However, he got to be coma, and died for respiratory failure at 41st day after radiotherapy. Autopsy was performed.

Result: Biopsy specimens showed immature tumor originating from epithelial and mesenchymal cell. Epithelial component consisted of basaloid cells, ductal cells and squamous differentiation. Mib‐1 index was over 30%. There were p16‐positive cells and HPV‐RNA‐ISH was partially positive. In autopsy, intranasal specimens showed necrotic changes. Therefor intracranial specimens showed same pathological findings as biopsy.

Conclusion: We performed radiotherapy alone for HMSC with intracranial invasion. This is the 1st HMSC report about the efficacy of radiotherapy comparing biopsy and autopsy pathology. Radiotherapy has some effectiveness in HMSC, especially sinonasal lesion.

Symposium 30: S30‐1

Molecular mechanisms underlying mammalian‐specific neocortical development and evolution

Tadashi Nomura

Developmental Neurobiology, Kyoto Prefectural University of Medicine

The mammalian neocortex is a conspicuous brain structure characterized by a six‐layered laminar organization. During neocortical development, excitatory projection neurons migrate toward the brain surface by changing their shapes from multi‐polar to bi‐polar morphology, which accomplishes an inside‐out pattern of cortical development. Deleterious changes in genetic and environmental factors significantly affect neuronal migration and consequence congenital cortical abnormalities. In contrast, a six‐layered neocortex does not develop in non‐mammalian species: all neurons exhibit multi‐polar shape and organize a three‐layered dorsal cortex in reptiles. However, molecular mechanisms underlying species‐specific neuronal migration and cortical organization remain unclear. Here we identify that species‐dependent regulation of Wnt signaling plays an essential role in mammalian and reptilian corticogenesis. Temporal controls of Wnt signaling in migratory neurons are crucial for multipolar‐to‐bipolar conversion in mammals, and manipulation of Wnt signaling activity phenocopied species‐specific neuronal morphologies. We suggest that heterochronic changes in Wnt activity contributed to the evolution of mammalian‐type neuronal migration and an inside‐out pattern of corticogenesis.

S30‐2

Hippocampal neurogenesis during development and aging in human

Homa Adle‐Biassette^1,2,3; Sara Cipriani²; Isidre Ferrer⁴; Eleonora Aronica⁵; Gabor Kovacs⁶; Philippe Manivet^2,3; Pierre Gressens²

¹Department of Pathology, Lariboisiere Hospital, APHP, Paris, France; ²PROTECT, INSERM, Paris Diderot University, Sorbonne Paris Cite, F‐75019 Paris, France; ³Plateforme de Bio‐Pathologie et de Technologies Innovantes en Sante, Centre de Ressources Biologiques, BB‐0033‐00064, Lariboisiere Hospital, APHP, Paris, France; ⁴Department of Pathology and Experimental Therapeutics, University of Barcelona, Bellvitge Campus; ⁵Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ⁶Institute of Neurology, Medical University of Vienna, Vienna, Austria

The main steps of the formation of the DG have been largely studied in rodents. Adult neurogenesis remains controversial in human. We characterized the progenitor subtypes, cell fate molecules and the dynamics of neurogenesis of the human hippocampal formation from the embryonic period to adulthood, including in patients with Alzheimer's disease (AD). The Ammon's horn includes two germinal compartments, the ventricular zone containing ventricular radial glial cells (RGC) and the subventricular zone containing unipolar RGC cells and TBR2‐positive intermediate progenitor cells (IPC). Pyramidal layers are generated with the “inside‐out” pattern but show differences in layer segregation between the ammonic and subicular plates. RGC density declines with neurogenesis from mid‐gestation until the perinatal period. The DG forms from two matrices. The secondary dentate matrix surrounds the dentate anlage and contains unipolar and multipolar RGC and IPC. By GW16, when the granule cell layer can be delineated, a hilar matrix and the subgranular zone (SGZ) become identifiable containing unipolar RGC and IPC. Dentate neurons are generated with the “outside‐ in” pattern. Around the perinatal period, the dense network of RGCs in the SGZ starts to decrease in density, but neurogenesis persists during childhood, few Doublecortin‐positive cells are seen in adults. The DG of both control and AD individuals shows Nestin‐positive and/or GFAP‐delta‐positive cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems minor in the adult. Supported by European Commission FP7‐ HEALTH‐2011‐2.2.2‐2/Develage

S30‐3

Normal and abnormal CNS development: new insights with fetal ultrasound

Ritsuko Kimata Pooh

CRIFM Clinical Research Institute of Fetal Medicine PMC

Fetal CNS is remarkably developing in the first trimester and changing its appearance from premature tubal structure to the bilateral cerebri, cerebellum and brainstem. Neuro‐sonoembryology has been improved with great advances of 3D ultrasound technology such as HDlive silhouette technology and studio‐live technology. However, detectable CNS abnormalities are limited in the first trimester because neuronal migration and proliferation will take place from 3rd or 4th months of gestation. From the early second trimester, the brain structure is clearly observed by ultrasound and most of congenital brain anomalies can be detected but it is quite hard to detect neuronal migration disorders during pregnancy. Phenotype of migration disorders in the cortex conspicuously appears after 28 weeks of gestation when cortical gyration/sulcation is clearly visualized. It has been believed that it is quite hard to detect migration disorder before 28 weeks. However, in most cases with neuronal migration disorder, neurological prognosis is not favorable. “Early detection of migration disorder before gyration” is one of our important missions. From our experience, early diagnoses of migration disorder have been possible by using transvaginal high‐resolution 3D ultrasound from early second trimester by observation of Sylvian fissure appearance, abnormal early sulci, irregular ventricular wall, and persistent ganglionic eminence. Close observation of those brain structural changes in detail is not generally performed however it might help to establish a new field of fetal neuroscience.

S30‐4

A continuing role for morphology in a multidisciplinary environment

Brian Harding^1,2

¹University of Pennsylvania; ²Department of Pathology, Children's Hospital of Philadelphia

Advances in medical imaging and genetic knowledge have become so impressive of late that there is a tendency to neglect the acquisition of detailed histomorphologic information. A variety of examples taken from my personal practice, both with and without genetic diagnosis or specific imaging features, will serve to demonstrate the continuing importance of neuropathologic studies in defining new entities and formulating pathogenetic hypothesis. In the past a disorder was often first categorized in morphologic terms; but even today, neuropathologic findings may herald the emergence of a novel disorder when clinical and imaging studies are inconclusive and genetic information lacking. Reference will be made to both published and unpublished case material that reflects this situation.

Oral 15: O15‐1

Pathological characteristics and anti‐acid staining of non‐tuberculous brain infection

Jing Gao^1,2; Chenhui Mao^1,2; Hang Shen²; Jing Yuan²; Qiwen Yang³; Yi Guo⁴; Liangrui Zhou⁵; Feng Feng⁶; Fang Li⁷; Bin Peng²

¹Neurological Department Neuropathological Lab Peking Union Medical College Hospital; ²Neurologixal Department Peking Union Medical College Hospital; ³Department of Clinica Laboratory Peking Union Medical College Hospital; ⁴Neursurgical Department Peking Union Medical College Hospital; ⁵Pathological Department Peking Union Medical College Hospital; ⁶MTI Centre Peking Union Medical College Hospital; ⁷PET Centre Peking Union Medical College Hospital

Introduction: acid‐fast staining can detect Mycobacterium, actinomycetes, Legionella micdadei; some cell inclusion . We report 6 brain biopsy cases with subacute multiple intracranial infection related with acid‐fast staining.

Methods: for HE slides with inflammation, 100X microscope observation must be done. When the neutrophils were found, the Gram staining, acid‐fast staining and modified acid‐fast stain were the first choice, then PAS, silver staining, CD3, CD20, CD68 are carried out. close cooperate with microbiologist and genetic analysis.

Results: 6 cases were male 3, female 3, age 22‐44. All biopsy has neutrophils. 5 cases were diagnosed as non‐tuberculosis infection, followed up for years: 2 McMahon cocci, 2 nocardosis and 1 atypical mycobacterium. Two cases were misdiagnosed as TB for acid‐fast stain positive. Three cases were misdiagnosed as inflammatory demyelination. 4 cases of suspected pathogens were found under 100X microscope, 3 of them with gram / acid‐fast /modified acid‐fast staining positive and 1 with negative staining were confirmed as atypical mycobacterium by the culture and genetic analysis. There were 1 TB cases without pathogen under microscope confirmed by culture. There was no significant difference between T and B cells. All the patients have no typical multinucleated giant cells. Creutzfeldt cell can be seen.

Conclusion: neutrophils in brain biopsy are an important sign of infection. The acid ‐ fast staining should be combined with GAM, modified acid‐fast satin and PAS for diagnosis differenciation. 100X is very important for the microscopic observation of brain infection. Inflammation and demyelination are also common in infectious diseases.

O15‐2

Invasive aspergillosis of paranasal sinuses with orbitocranial and brain extensive extension

Erick Gomez‐Apo¹; Alejandro Bonilla‐Mendez¹; Mario Gamez‐Rosales¹; Eric Mendoza‐Oviedo¹; Marisol Vaca‐Segura¹; Teresa Del‐Angel‐Arenas¹; Myrna Arrecillas‐Zamora¹; Rogelio Trevino‐Rangel²; Alexandro Bonifaz¹; Laura Chavez‐Macias¹

¹General Hospital of Mexico; ²Department of Microbiology, School of Medicine, UANL

Background: Chronic invasive fungal sinusitis is a rare subtype of mycotic diseases. It is characterized by a slow onset. Usually occurs in immunocompromised patients and is almost always lethal without early treatment.

Clinic Case: A forty‐two‐year‐old man. He began four months before of death with headache, decreased view, increased volume of right orbit and nose, nasal secretion, anosmia and loss of 15 pounds in a month. He continued with bilateral amaurosis, absent bilateral pupillary reflexes, purulent ocular secretion and very marked exophthalmos. Diagnosis on RMN was esthesioneuroblastoma; biopsy was taken, the diagnosis was hyalohyphomycosis (fungus ball); he was treated with Amphotericin and Voriconazole; he continued with deterioration and died.

Autopsy Findings: The findings of autopsy were extensive destruction of orbitofrontal skeleton, ethmoid and sphenoid paranasal sinuses, with green exudate in ventral surface of frontal lobes with extension and destruction of cerebral parenchyma with abscess formation. On biopsy and autopsy, there were mycotic structures with Aspergillus features. On mycologic study, it was identified not‐pigmented fungus with very slowly‐growing in culture media. Molecular study was realized with final diagnosis of Aspegillus nidulans / Emericella nidulans infection.

Conclusion: Rhinonasal disease with intracranial extension is the commonest pattern of Aspergillus infection followed by intracranial mass lesions. Craniocerebral aspergillosis in immunocompetent hosts has three patterns of presentation that seem to correlate with clinical outcomes. Intracerebral aspergillosis is associated with the worst clinical outcome. Patients with orbital and cranial base aspergillosis had good recovery.

O15‐3

Leprosy and Buruli ulcer ‐ mycobacterial diseases with painless skin lesions

Masamichi Goto¹; Junichiro En²

¹National Sanatorium Hoshizuka‐Keiaien, Kagoshima, Japan; ²International University of Health and Welfare, Chiba, Japan

Introduction: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. M. leprae injures peripheral nerves and cause multiple mononeuropathy. Buruli ulcer is also a mycobacterial disease caused by M. ulcerans. Deep skin ulcers are formed, but curiously the ulcers are usually painless, that may lead to diagnostic delay. We compared the peripheral nerve pathology of these diseases.

Methods: Human skin biopsy specimens of leprosy and Buruli ulcer, footpads of M. leprae‐inoculated nude mice, footpads of M. ulcerans‐inoculated BALB/c mice were histologically evaluated. M. ulcerans produces toxic lipid mycolactone, thus footpads of mycolactone‐injected BALB/c mice and Schwann cell lines exposed to mycolactone were also evaluated.

Results: In the nerves of early skin lesions of human lepromatous leprosy, unmyelinated Schwann cells were the main host cells of M. leprae, and in nude mice model M. leprae were observed mainly in macrophages. In M. ulcerans‐inoculated mice, the bacilli invaded perineurium with vacuolar change of myelin sheaths. Von‐Frey sensory test showed diminished pain response [Goto, Am J Pathol 2006]. Mycolactone‐injected mice also showed similar findings [En, Infect Immun 2008]. Finally, mycolactone showed higher toxicity to cultured Schwann cells (SW10) than that to fibroblasts (L929) and macrophages (J774) [En, PLOS Negl Trop Dis 2017].

Conclusion: In leprosy, M. leprae selectively invaded Schwann cells and macrophages, but in Buruli ulcer, M. ulcerans did not show such specific tropism. As mycolactone showed high toxicity to Schwann cells, mycolactone is suggested to be responsible for the painless nature of Buruli ulcer.

O15‐4

Progression of neuropathology of Creutzfeldt‐Jakob disease and its relation to clinical findings

Yasushi Iwasaki; Akio Akagi; Maya Mimuro; Hiroaki Miyahara; Mari Yoshida

Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: To improve understanding of Creutzfeldt‐Jakob disease (CJD) through a clinicopathological investigation, we conducted an investigation of the clinical progression of CJD and its relation to cerebral cortical pathology.

Methods: Forty‐three cases of MM1‐type sporadic CJD were included in the study. The average age at onset was 69.7 years, and the average disease duration was 13.5 months.

Results: The earliest pathologic finding was spongiform change and the next was gliosis. Neuropil rarefaction subsequently appeared, followed by neuron loss. Based on these observations, we proposed the following stages of cerebral cortical pathology (stage I to VI): Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We found a statistically significant correlation between disease duration and stage. All diffusion‐weighted brain magnetic resonance imaging‐examined cases showed cortical hyperintensity at the time of first imaging (average of 1.6 months after onset). Myoclonus and periodic sharp‐wave complexes were first observed on electroencephalograms at an average of 2.1 months and 2.2 months, respectively, after onset. The akinetic mutism state was observed 3.2 months after onset on average.

Conclusion: The cortical hyperintensity seen on diffusion‐weighted images is a better indicator of spongiform changes than of gliosis. The first observation times of cortical hyperintensity, myoclonus, and periodic sharp‐wave complexes approximately correspond to the early phase of Stage II. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II.

Oral 16: O16‐1

Insights from biochemical analyses of regional distribution of Alzheimer's pathologies

Mitsuru Shinohara^1,2; Naoyuki Sato¹; Dennis W Dickson²; Guojun Bu²

¹National Center for Geriatrics and Gerontology, Aichi, JAPAN; ²Mayo Clinic, Jacksonville, FL, USA

Introduction: Region‐specific appearance of Alzheimer's pathologies, including Aβ and tau, has provided important clues to understand the disease pathogenesis. While region‐wide analyses were mostly done by clinical imaging studies or postmortem microscopic studies, we performed biochemical analyses through introducing in‐house ELISAs.

Methods: The amounts of Aβ, tau, apoE and other molecules related to Aβ metabolism or neurodegeneration were measured in twelve brain regions, including neocortical, limbic and subcortical areas from different stages of disease cases. We analyzed regional associations between these molecules together with difference in absolute amounts between groups.

Results: The regional distribution of full‐length Aβ, which were liable to accumulate in neocortical areas, positively associated with synaptic markers, and negatively associated with soluble apoE and an astrocytic marker, suggesting the potential involvement of synases, and apoE or astrocytes in Aβ accumulation (Shinohara et al., Acta Neuropathologica 2013). However, such associations were changed in familial Alzheimer's disease cases with mutations in APP or PSEN1, suggesting that different pathomechanism causes distinct regional Aβ accumulation (Shinohara et al., Brain 2014). N‐terminally truncated Aβ42, represented by pyroglutamylated Aβ11‐42, whose levels were increased in the symptomatic stage, were liable to accumulate in some limbic areas, and strongly associated with accumulation of tau and apoE, suggesting the critical roles of N‐terminally truncated Aβ42 in the disease progression (Shinohara et al., Brain 2017).

Conclusions: These results showed utility of our biochemical method analyzing the regional distribution of Alzheimer's pathologies to address the disease pathogenesis. Furthers studies are now underway and will be discussed.

O16‐2

The presence of Aβ toxic conformer in the inferior parietal cortex before Aβ plaque formation and its dynamic localization in aging

Yusuke Kageyama^1,4; Olga Pletnikova¹; Gay L Rudow¹; Ikuo Tooyama⁴; Kazuma Murakami⁵; Kazuhiro Irie⁵; Susan M Resnick⁶; David R Fowler⁷; Lee J Martin^1,2; Juan C Troncoso^1,3

¹Department of Pathology, The Johns Hopkins University School of Medicine; ²Department of Neuroscience, The Johns Hopkins University School of Medicine; ³Department of Neurology, The Johns Hopkins University School of Medicine; ⁴Molecular Neuroscience Research Center, Shiga University of Medical Science; ⁵Division of Food Science & Biotechnology, Graduate School of Agriculture, Kyoto University; ⁶Laboratory of Behavioral Neuroscience, NIH/NIA/IRP; ⁷Maryland Office of the Chief Medical Examiner

Introduction: Amyloid beta (Aβ) plays a critical role in the pathogenesis of amyloidopathies, notably Alzheimer's disease (AD). Solid‐state NMR analysis has identified a particular Aβ conformation which forms oligomers and is neurotoxic.

Methods: We used the 11A1 antibody that targets this toxic conformer, to examine its distribution with immunofluorescent staining in the postmortem parietal cortex of 35 human subjects, 30 to 65 years of age, found histologically free of AD lesions.

Results: 11A1 immunoreactivity was found in cortical neurons, astrocytes, neuropil and perivascular spaces at 30 years of age. Approximately 85% of neurons and 75% of protoplasmic astrocytes showed 11A1 immunoreactivity, and those proportions of neurons and astrocytes remained stable with age. 11A1 immunoreactivity was identified in nearly 30% of perivascular spaces during the fourth and fifth decades. 11A1 immunoreactivity was present in the neuropil as 1‐2 µm particles. Imaging of neuropil 11A1 immunoreactive particle with vesicle markers showed colocalization limited to CD63, which was also detected in astrocytes but not in neurons. This finding suggests that astrocytes participate in the processing of the Aβ toxic conformer. Notably, in the sixth decade, at the same time that the proportion of perivascular spaces with 11A1 immunoreactivity declines to approximately 20%, the number of neuropil 11A1 immunoreactive particles sharply increased.

Conclusion: The Aβ toxic conformer is present in various cell types and brain structure in the inferior parietal cortex. Around age 50 years, this steady state of Aβ changes with a decrease of perivascular Aβ and a concomitant increase in neuropil Aβ.

O16‐3

Sushi repeat‐containing protein 1 co‐accumulates with cerebrovascular Abeta deposits in cerebral amyloid angiopathy

Yasuteru Inoue¹; Mitsuharu Ueda¹; Masayoshi Tasaki¹; Akari Takeshima²; Yohei Misumi¹; Takayuki Kosaka¹; Taro Yamashita¹; Hitoshi Takahashi²; Akiyoshi Kakita²; Yukio Ando¹

¹Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ²Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

Introduction: Sporadic cerebral amyloid angiopathy (CAA)is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhage and dementia. Several molecules have reportedly co‐accumulated with tissue amyloid deposits in patients with amyloidosis. The exact molecules that co‐accumulate with cerebrovascular Aβ deposits are still not fully known. Here, to identify the key molecules in CAA diagnosis and pathogenesis that may lead to therapy for CAA, we used laser capture microdissection to perform proteomic analyses with cerebral blood vessels.

Methods: We performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and determined the levels of highly expressed proteins in cerebral blood vessels in CAA.

Results: We focused on sushi repeat‐containing protein 1 (SRPX1), which is specifically expressed in CAA‐affected cerebral blood vessels. Immunohistochemical studies revealed that SRPX1 co‐accumulated with Aβ deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co‐accumulated with Aβ deposits in senile plaques. Furthermore, we demonstrated that both Aβ40 and Aβ42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aβ40. Knockdown of SRPX1, in contrast, reduced the formation of Aβ40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells.

Conclusion: SRPX1 may be a novel molecule that is up‐regulated in cerebrovascular Aβ deposits and that may increase Aβ‐induced cerebrovascular degeneration in CAA.

O16‐4

Sex and age interact to determine clinicopathologic differences in Alzheimer's disease

Amanda M. Liesinger¹; Neill R. Graff‐Radford²; Ranjan Duara³; Kelly M. Hinkle¹; Fadi S. Hanna Al‐Shaikh¹; Sarah K. DiLello¹; McKenna F. Johnson¹; Dennis W. Dickson¹; Melissa E. Murray¹

¹Neuroscience Department, Mayo Clinic, Jacksonville, FL; ²Neurology Department, Mayo Clinic, Jacksonville, FL; ³Wein Center for Alzheimer's Disease and Memory disorders, Mount Sinai Medical Center, Miami Beach, FL

Women reportedly make up two‐thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi‐Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53‐102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and med did not differ. Men were younger at age onset, had a shorter disease duration, and more often had atypical (non‐amnestic) clinical presentations. The frequency of autopsy‐confirmed AD among women and men stratified by age at death revealed an inverse U‐shaped curve in men and a U‐shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional densities of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of tangle density compared to men, especially in the hippocampus. Men and woman did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically confirmed AD has the same frequency in women and men, but their clinical presentations ages at onset tend to differ.

Asian Diagnostic Slide Session 1: Case 1

Oligodendroglioma, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation of a 31‐year‐old male: A case report and literature review

Yangki Minn¹; Seonghye Choi²; Se Hoon Kim³; Yoon Jin Cha⁴

¹Department of Neurology, Hallym Univeristy College of Medicine, Kangnam Sacred Heart Hospital, Seoul, Korea; ²Department of Neurology, Inha University College of Medicine, Inha Hospital, Incheon, Korea; ³Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea; ⁴Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea

Introduction: Oligodendroglioma (OLG) is a diffusely infiltrating glial neoplasm. Sporadic case reports of neuronal differentiation of OLG and subset of neuronal gene expression of OLGs have been identified. Here, we report a rare case of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation in a 31‐year‐old male patient.

Clinical summary: A 31‐year‐old male patient without specific medical history was admitted with a seizure. Brain computed tomography revealed 7cm‐sized contrast enhancing cystic mass with internal necrosis and calcification, in the right frontal lobe. With suspicion of anaplastic OLG, gross total removal of the tumor was performed. Patient is alive well after subsequent radiotherapy.

Pathologic findings: On microscopic examination, diffusely infiltrating tumor cells with clear cytoplasm were found in the cortex. Necrosis or endovascular proliferation was not found. Majority of tumor was composed of OLG‐like clear tumor cells with chicken‐wire pattern vasculatures. Throughout the tumor, atypical gangliocyte‐like cells having hyperchromatic nulcei, prominent nucleoli and ample cytoplasm were observed. Differential diagnoses included ganglioneuronal tumors and OLG with gangliocytic differentiation. Tumor cells were diffusely positive for OLIG2 and IDH (R132H) immunohistochemical stainings (IHC). Scattered ganglion‐like cells were highlighted by NeuN and synaptophysin IHC. Subsequent fluorescence in situ hybridization analysis revealed 1p/19q codeletion, confirmed the diagnosis of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation.

Conclusion: Although rarely found, OLG can have neuronal differentiation and may present like long‐term epilepsy associated tumor and lead to underdiagnosis. IDH analysis, preferentially IDH1 IHC would help to discriminate OLG from other glioneuronal tumors.

Case 2

A Pediatric Case of Left Frontal Hemorrhagic Tumor Radiographically Diagnosed as Leukoencephalopathy with Calcification and Cysts

Ryuta Saito¹; Masayuki Kanamori¹; Mitsugu Uematsu²; Mika Watanabe³; Teiji Tominaga¹

¹Department of Neurosurgery, Tohoku University Graduate School of Medicine; ²Department of Pediatrics, Tohoku University Hospital; ³Division of Pathology, Tohoku University Hospital

Introduction: Leukoencephalopathy with calcifications and cysts (LCC) is a rare disease in which parenchymal cysts and calcifications within a widespread leukoencephalopathy can cause a broad spectrum of neurological symptoms. It is now recognized as a cerebral microangiopathy caused by mutations in SNORD118.

Case: 9 year‐old boy developed a sudden onset of generalized seizure and admitted to local hospital. MRI demonstrated blurring of corticomedullary junction at left frontal cortex and spotty T2 high intensity at left basal ganglia. As he had an episode of infection 1 month prior to disease onset, acute disseminated encephalomyelitis was suspected. Anti‐epileptic treatment was given at this time. Half an year later, he developed headache, anorexia, and vomiting. MRI obtained at this point revealed multicystic hemorrhagic mass with perifocal edema at his left frontal lobe. CT scan revealed calcification. Opthalmological examination revealed no abnormalities. With the radiological diagnosis of LCC, he was referred to pediatric department for genetic examinations of SNORD118 mutation, which turned out to be negative. After then, the lesion enlarged with multi‐stage hemorrhage and was subjected to surgical removal. Histological examination of removed mass revealed multicystic, calcified lesion with hemosiderosis and gliosis. Fibrinoid degeneration and hyalinization of the vascular wall was also found.

Discussion: The pathological diagnosis given for this case was microangiopathy. Though LCC was suspected, SNORD118 mutation was negative. We would like to ask for discussion regarding the final diagnosis.

Oral 17: O17‐1

Possible distinction of four repeat tau‐positive lesions of Alzheimer's disease and progressive supranuclear palsy probed by four repeat‐specific antibodies.

Momoko Ebashi^1,4; Miho Uematsu¹; Ayako Nakamura¹; Yoshinori Ito²; Katsuiku Hirokawa³; Satoshi Kamei⁴; Toshiki Uchihara¹

¹Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science; ²Yokuhukai Hospital; ³Nitobe Memorial Nakano General Hospital; ⁴Division of Neurology, Department of Medicine, Nihon University School of Medicine

Introduction: Accumulation of abnormal tau protein is the pathological hallmark shared between Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Their distinction is based on the distribution of tau‐positive neurons, associated cytopathology or tau isoforms. It is generally believed that 4 repeat (4R)‐tau lesions in AD and PSP are not readily distinguishable. In this study, we tried to distinguish immunorepresentation of 4R‐tau through comparison between two different antibodies toward 4R‐tau.

Methods: Thirteen autopsied brains (4 AD, 4 PSP and 5 AD+PSP) were enrolled in this study. 4R‐tau immunoreactivity probed either by polyclonal anti 4R‐tau® or monoclonal RD4® was compared in each case, and evaluated the structural characteristic of 4R‐tau.

Result: The anti 4R‐tau® labeled a larger number of AD‐neurofibrillary tangles (NFTs) more intensely than RD4®. This difference was evident in AD‐prone areas such as hippocampus and locus ceruleus (LC) that of RD4®, which is particularly highlighted in the hippocampus and LC in all 13 cases. In contrast, RD4® labeled a larger number of tuft‐shaped astrocytes (TAs) more intensely than anti 4R ‐tau®. This preferential immunoreactivity of RD4® on TA over anti 4R‐tau® was evident in PSP‐prone regions such as the precentral gyrus and brainstem tegmentum even if AD and PSP pathologies are coexistent, while NFT in PSP cases exhibited equivalent immunoreactivity to anti 4R‐tau® and RD4®.

Conclusion: Preferential RD4® immunoreactivity on TA/PSP is in contrast with complementary preference of anti 4R‐tau® on NFT/AD. This may provide a clue to clarify difference in molecular species of 4R‐tau between AD and PSP.

O17‐2

TDP‐43 pathology contributes to clinicopathological heterogeneity of corticobasal degeneration

Shunsuke Koga¹; Kouri Naomi²; Ronald L. Walton¹; Keith A. Josephs³; Neill Graff‐Radford⁴; Ryan J. Uitti⁴; Jay A. van Gerpen⁴; Zbigniew K. Wszolek⁴; Owen A. Ross¹; Dennis W. Dickson¹

¹Department of Neuroscience, Mayo Clinic; ²Department of Pathology, Boston Children's Hospital; ³Department of Neurology (Behavioural Neurology & Movement Disorders); ⁴Department of Neurology, Mayo Clinic

Introduction: Corticobasal degeneration (CBD) is a clinicopathologically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to examine whether transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology contributes to clinicopathologic heterogeneity of CBD.

Methods: Paraffin‐embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy‐confirmed CBD cases were screened with immunohistochemistry for phospho‐TDP‐43. In cases having TDP‐43 pathology, additional brain regions were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP‐43 pathology, and clinicopathologic and genetic features were compared between the clusters.

Results: TDP‐43 pathology was observed in 45% of CBD cases, most frequently in the midbrain tegmentum (80% of TDP‐43‐positive cases), followed by the subthalamic nucleus (69%). TDP‐43‐positive CBD was divided into TDP‐limited (52%) and TDP‐severe (48%) groups by hierarchical clustering analysis. TDP‐severe patients were more likely clinically diagnosed with PSP than TDP‐limited and TDP‐negative patients because of high frequency of downgaze palsy. Multivariable logistic regression model revealed that TDP‐43 pathology in the midbrain tectum was strongly associated with the downgaze palsy. In addition, tau burden in olivopontocerebellar structures was significantly greater in TDP‐43‐positive than TDP‐43‐negative CBD cases. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP‐severe (65%) than in TDP‐negative (89%) and TDP‐limited (91%) CBD cases.

Conclusion: TDP‐severe CBD is a distinct clinicopathologic subtype of CBD, which presents with PSP‐like presentations. Severe tau pathology in olivopontocerebellar structures may associate with this subtype.

O17‐3

Morphological features of neuronal and glial tau pathology in GGT (Types II and III)

Hidetomo Tanaka¹; Yasuko Toyoshima¹; Shinobu Kawakatsu²; Takeshi Miura^3,4; Takeshi Ikeuchi³; Osamu Onodera⁴; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University; ³Department of Molecular Genetics, Brain Research Institute, Niigata University; ⁴Department of Neurology, Brain Research Institute, Niigata University

Introduction: Globular glial tauopathy (GGT) is a new 4‐repeat tauopathy characterized pathologically by globular glial inclusions (GGIs), namely those affecting oligodendrocytes (GOIs) and astrocytes (GAIs). GGT is classified into three pathological subtypes (Types I, II and III), but the morphological features of the individual subtypes have not been investigated in detail. We have previously reported unique neuronal cytoplasmic inclusions (NCIs) in GGT Type III, but the morphological features of these NCIs are not included in the GGT consensus recommendations (Ahmed et al., 2013). Here, we investigated the morphological differences between the GGT subtypes, focusing on NCIs and GAIs.

Methods: We investigated the tau pathology in 5 cases of GGT (Type II, n = 2; Type III, n = 3) in terms of the immunohistochemistry, biochemistry, 3D structure, ultrastructure, and quantity of the tau‐positive inclusions.

Results: GAIs in Type II were large with radiating process‐like structures, whereas those in Type III were small with perikaryal large globular structures. 3D morphometric analysis supported the above findings. NCIs showed three unique subgroups in terms of shape: 1) diffusely granular, 2) thick and cord‐like, and 3) round and horseshoe‐shaped. Thick cord‐like NCIs were a feature in both types. Interestingly, the round/horseshoe‐shaped NCIs were observed only in Type III.

Conclusions: The present findings suggest that morphological differences among GAIs may be a new feature to support classification of the subtypes, and that the presence of characteristic NCIs is a new common feature of GGT.

O17‐4

Sequential distribution patterns of aging‐related tau astrogliopathy (ARTAG) in the human brain

Gabor G. Kovacs^1,2; Sharon X. Xie³; John L. Robinson²; Edward B. Lee²; Douglas H. Smith⁴; Theresa Schuck²; Virginia M.‐Y. Lee²; John Q. Trojanowski²

¹Institute of Neurology, Medical University of Vienna, Vienna, Austria; ²Center for Neurodegenerative Disease Research (CNDR), Institute on Aging and Department of Pathology & Laboratory Medicine; ³Department of Biostatistics and Epidemiology; ⁴Department of Neurosurgery, Center for Brain Injury and Repair, the Perelman School of Medicine (PSOM) at the University of Pennsylvania, Philadelphia, PA, USA

Introduction: Aging‐related tau astrogliopathy (ARTAG) describes tau pathology in astrocytes in different locations and anatomical regions. In the present study we addressed the question of whether sequential distribution patterns can be recognized for ARTAG.

Methods: By evaluating 687 postmortem brains with diverse disorders we identified ARTAG in 455. We evaluated frequencies and hierarchical clustering of anatomical involvement and used mathematical and statistical approaches to model the sequential distribution of ARTAG and astroglial tau pathologies across different brain regions.

Results: For subpial and white matter ARTAG we recognize three and two patterns, respectively, each with two stages initiated or ending in the amygdala. Subependymal ARTAG does not show a clear sequential pattern. For grey matter (GM) ARTAG we recognize a striatal pathway of spreading bidirectionally towards the cortex and/or amygdala, or the brainstem and an amygdala pathway, which precedes the involvement of the striatum and proceeds bidirectional spread towards the cortex or the brainstem.

Conclusion: Tau‐astrogliopathy type‐specific sequential patterns require the consideration of complex relationships of various tau pathologies and therefore cannot be simplified as neuron‐based staging systems alone.

Oral 18: O18‐1

Autopsy on home‐cared patients with neurological disorders. Nitobe model to improve patient care, medical education and research

Toshiki Uchihara¹; Shuta Toru¹; Michio Yamane²; Hiroshi Shintaku^3,4; Masanobu Kitagawa⁴; Katsuiku Hirokawa³; Tetsuya Irie²

¹Neurology, Nitobe Memorial Nakano General Hospital; ²Internal Medicine, Nitobe Memorial Nakano General Hospital; ³Pathology, Nitobe Memorial Nakano General Hospital; ⁴Pathology, Tokyo Medical and Dental University

Introduction: Decline in the rate and number of autopsy is accelerating in all countries. Cost‐conscious management of patients further accelerates this decline. Because increasing number of patients are cared for outside of hospital such as home or institutions for chronic care, autopsy on these individuals deceased outside of hospital may counteract this decline.

Method: Nitobe model to support autopsy on these patients was constructed based on financial supports by several private grants. This Nitobe model includes autopsy units (Nitobe Memorial Hospital and Tokyo Medical and Dental University Hospital) and a support center to afford the cost for autopsy (3,000 USD/autopsy) and transport of the deceased.

Results: Among 31 patients autopsied in this project, 3 deceased at home and 28 deceased at hospital after 2.1 yr (mean) of home care. This cohort included 9 ALS, 8DLB, 4PSP, 3AD, 2MyD, MSA, CBD, pure autonomic failure, leukoencephalopathy and cerebral hemorrhage. Some of the home care physicians became interested in examining the autopsy samples by themselves and in presenting the data in CPC or even in this meeting. Some of the patients’ family or even patients themselves gave consent for autopsy during life.

Conclusion: Autopsy on the deceased at home is a feasible strategy that can improve the quality of care. Increasing the number of autopsy may strengthen the scientific basis for medical education and research. Public financial support is indispensable to expand this Nitobe model so that similar system is available all over Japan or in the world.

O18‐2

Introducing the Digital Brain Tumor Atlas (DBTA), a freely available repository for brain tumor whole slide scans

Thomas Roetzer^1,2; Anna‐Christina Moser^1,2; Petra Mercea^2,3; Romana Prihoda^2,3; Baran Atli^1,2; Johannes A. Hainfellner^1,2; Bernhard Baumann⁴; Georg Langs⁵; Adelheid Woehrer^1,2

¹Institute of Neurology, Medical University of Vienna, Vienna, Austria; ²Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; ³Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; ⁴Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; ⁵Computational Imaging Research Lab, Department of Biomedical Imaging and Image‐guided Therapy, Medical University of Vienna, Vienna, Austria

Introduction: Digital pathology is increasingly recognized as useful tool for precision diagnostics. Typical tasks include tissue segmentation, disease classification, and enhanced prognostic rating. Yet, the underlying machine learning algorithms depend on the availability of large, freely available datasets for training. However, there are only few whole slide image (WSI) repositories available online, and those do not cover all brain tumor types in sufficient quality and quantity.

Methods: Herein, we introduce the Digital Brain Tumor Atlas, which will comprise all brain tumor entities according to the current WHO classification. Using MedUni Vienna's neurobiobank as resource, we are in the process of scanning a total of 10,000 expert‐selected H&E slides in high resolution using a Hamamatsu NanoZoomer XR scanner. All slides will be published online together with basic clinical annotations.

Results: So far, we have digitized roughly 2,500 WSI covering 100 different brain tumor types. In parallel, information on gender, location, and age has been collected for all cases. For a subset of 500 glioma cases, we have further manually segmented tumor, necrotic and hemorrhagic areas.

Conclusions: We introduce the Digital Brain Tumor Atlas, a freely available online repository for H&E slide scans of all brain tumor entities. The atlas will fill a critical gap and prove valuable 1. for training machine learning algorithms for enhanced diagnostics 2. as a training tool for young neuropathologists, and 3. as an independent, external validation dataset for digital pathology projects.

O18‐3

Allied neurosurgical results World War I and II

John Hedley‐Whyte

Harvard University

Introduction: In 1941 Major, later Sir Benjamin Rycroft was teaching me to read. I asked “Why do the eye cases come to you while the neurosurgical cases are flown to Oxford?” “Neurosurgery is harder than the eye business. They are flown with catheters draining their spinal fluid.” “Why?” “So they do not burst their brains.” “Who thought that up?” “Cushing in Boston. He trained all the head doctors: Cairns at Oxford, Ross at Barts.”

Methods: Harvard, Yale, Oxford and U.S. Library of Congress Archives and other sources were examined.

Results: In World War I Allied mortality from head injury was reduced from 37% to 20% after King George V in 1915 gave Harvey Cushing de facto control. His pupil, Sir Hugh Cairns, halved it to 10% in WWII. His transport protocol remains a modern standard of care, but required 10,000 DC3s, C47s, Dakotas and UK and US Nurse Air Nightingales and 130 Air Landing Strips, newly constructed in Europe alone. The Allied World War I and II Medical and Surgical Services were under the control of Presidents Wilson and FD Roosevelt and Kings George V and VI.

Conclusion: Cushing's 3‐volume biography of Sir William Osler won a Pulitzer Prize. The Cushings were married from the Regius and Lady Osler's Oxford home. Before the Cushings’ honeymoon it was arranged that President Teddy Roosevelt would give the Romanes Lecture on June 7, 1910 at Oxford University. Friendly relations with Japan were espoused.

O18‐4

In order to keep neuropathology succession, teaching stuffs of neuropathology should deal with neuroanatomy, clinical clerkship, and clinical office for outpatients, as well as neuropathology

Shinsuke Kato; Shinichiro Kitao; Masahiro Ii; Hiroshi Kohama; Kosuke Yonekura; Yuki Kaida; Norihisa Itaki; Junko Yasui; Kana Oda; Keiko Kato

Division of Neuropathology, Tottori University Faculty of Medicine

Introduction: Our Neuropathology Division has expanded the field of clinical and practical medicine dealing with patients in addition to basic medical sciences, since we founded a neuropathology clinical office for outpatients in Tottori University in 2013.

Methods: With respect to the education of the basic medicine, we have succeeded for students to learn smoothly neuropathology by our lecturing neuroanatomy. Regarding the education of the clinical medicine, in order to bring up the sixth‐year medical students to be the physicians who want to major in neuropathology in the future, we educate outpatient clinic as one part of clinical clerkship. Around 2‐4 third‐year students study neuropathology during one month as Laboratory Assignment System (LAS).

Results: As for the neuroanatomy, we deliver 20 hour‐Lecture, perform 12 hour‐BrainCutting practice, and instruct 3 hour‐Tissue Observation training. Referring the neuropathology, 13 hour‐Lecture and 15 hour‐Tissue Observation training are carried out. Concerning the clinical clerkship, we teach the autopsy and surgical neuropathology as a routine. When we conduct an outpatient clinic, we make clinical‐clerkship students attend the clinic with patients and physicians, and have them learn pathologic findings. Synchronously, we make these students understand that the patients are able to receive pathology services of high quality through the clinic. As excellent results of LAS, one student published English paper and one student passed USMLE Step1.

Conclusion: In order to keep the succession to neuropathology in Medical University, it is necessary that neuropathologists deal with neuroanatomy, neuropathology, clinical clerkship, and outpatient clinic as high‐quality diagnostic services.

Asian Diagnostic Slide Session 2: Case 3

Diffuse leptomeningeal glioneuronal tumor exhibiting 1p/19q co‐deletion and H3F3K27M mutation: A rare case with unique molecular profile

Kavneet Kaur; Aruna Nambirajan; Prit Benny Malgulwar; Vaishali Suri; Mehar Chand Sharma; Ajay Garg; Chitra Sarkar

Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi

Introduction: Diffuse leptomeningeal glioneuronal tumour is a new entity in the recent WHO classification of CNS tumors (2016). It is a rare tumour characterised by predominant and widespread involvement of leptomeninges with olidodendroglial like cytology. Most are low grade, a small proportion show aggressive behaviour. Hence, a definite WHO grade is not yet assigned.

Clinical Summary: A 13‐year‐old female child presented with complaints of diminution of vision in both the eyes and headache for 1 year and paraplegia with bladder and bowel dysfunction for 1 month. MRI revealed an intadural extramedullary mass in D1‐D4 region of spinal cord and multiple T2 hyperintense lesions in sulcal spaces of cerebellum, choroid plexus of lateral ventricles, putamina and pons.

Pathological findings: Biopsy from a mass in the conus region showed a tumour with oligodendroglia like cytology and glomeruloid vessls with moderately high MIB1 index. The tumour cells were immunopositive for GFAP, synaptophysin, NeuN while negative for IDH and showed retained ATRX expression. The tumor was found to harbour 1p/19q co‐deletion by Fluorescence in‐situ hybridisation and H3F3A mutation by Sanger‐sequencing. IDH mutations and BRAF alterations were not found by sequencing and RT‐PCR, respectively. Based on overall findings, a diagnosis of diffuse leptomeningeal glioneuronal tumour was rendered.

Conclusions: Diffuse leptomeningeal glioneuronal tumors represent a distinct clinico‐pathological entity. Even though histologically benign, they can show aggressive behavior due to involvement of wide area of leptomeninges, development around the brainstem and difficulty in surgical intervention. Hence, a knowledge of this new entity is imperative to arrive at the correct diagnosis.

Case 4

38‐year‐old female with right parietal lobe mass lesion

Yue‐Shan Piao; Zhuo Li; Lei‐Ming Wang; Dan‐Dan Wang; Yong‐Juan Fu; De‐Hong Lu

Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Beijing, China

A 38‐year‐old female began to show paroxysmal left‐sided numbness more than 5 months ago. Her symptom spontaneously relieved after 1‐2 minutes each time,without physical weakness and hallucinations. No disturbance of consciousness, nausea and vomiting. The patient felt uncomfortable before each attack, but it cannot be clearly stated. The patient visited orthopedics over 3 months ago. Cervical MRI showed no obvious abnormality. Then, the examination of head CT taken 11 days ago indicated a low density in the right basal ganglia, parietal lobe and temporal lobe, which was considered as space‐occupying lesion. A cranial MRI showed a right parietal lobe mass lesion, being likely low‐grade glioma.

The patient was admitted to the department of neurosurgery and the tumor was completely removed under the microscope (5cm×4cm×3cm).

Histopathologically, there is low grade diffuse glioma with infiltration to the cortex, showing both astrocytic and oligodendrocytic differenciations. A few mitosis but no necrosis and vascular prolifration were noted. Immunohistochemically, the tumor cells were positive for GFAP, olig2, IDH1R132H and overexpression of p53 (60%), but negative for ATRX. The ki‐67 index was about 10%. PCR‐based direct sequencing determined the mutation of IDH1(R132H) and wild type of TERT promoter. FISH revealed 1p and 19q codeletion.

Morphological diagnosis of mixed oligoastrocytoma, WHO grade II was made. But, we couldn't make the integrated diagnosis according the revised version of the WHO classification of tumors of the central nervous system (2016 edition).

Our case suggested that there was a true “oligoastrocytoma” with both molecular features of astrocytoma and oligodendroglioma.

Case 5

A case of pediatric high grade glioneuronal tumor, NEC

Jiro Akimoto¹; Nobuyuki Nakajima¹; Norio Ichimasu¹; Michihiro Kohno¹; Yukiko Shishido‐Hara²; Jun Matsubayashi²; Toshitaka Nagao²; Sumito Nobusawa³; Junko Hirato³; Hideaki Yokoo³

¹Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan; ²Department of Human Pathology, Tokyo Medical University, Tokyo, Japan; ³Department of Patholofy, Graduate School of Medicine, Gunma Univeristy, Gunma, Japan

A 7‐year‐old girl presented with 4 months history of gradually worsening headache and nausea. On admission, she presented with left hemiparesis. CT and MRI demonstrated a large right temporo‐parietal cystic tumor with mural nodule, which was strongly enhanced by Gd‐DTPA. Our pre‐operative diagnosis was pilocytic astrocytoma or pleomorphic xanthoastrocytoma, and underwent 2‐stage total resection of the nodule and cyst wall of the tumor was undertaken. The tumor consisted of three histopathological components (A‐C). Part (A) displayed proliferation of pleomorphic astrocytes with moderate cellularity with high mitotic index. Microvascular proliferation and micro‐necrosis were also seen. Part (B) showed dense proliferation of small tumor cells with scant cytoplasm, presenting biphasic patterns. Part (C) included small tumor cells with neuronal differentiation on neuropil‐like matrix. Part (A) was immuno‐positive for GFAP, S100 and Olig‐2, and negative for IDH‐1 and neuronal markers. In contrast, Part (C) was negative for GFAP and positive for neuronal markers. Ki‐67 labeling index was 60‐70% in Part (A), but minimum in Part (B) and (C). Molecular analysis demonstrated only CDKN2A/B homozygous deletion, without IDH1/BRAF/H2F3A/FGFR1/ TERT promoter mutations. According to these histological findings, post‐operative 54Gy / 30Fr extended focal irradiation was undertaken, and her symptoms were gradually improved. Our integrated diagnosis of this case is a pediatric high grade glioneuronal tumor, NEC. Discussion about the histo‐pathological diagnosis of this rare tumor is requested.

Asian Diagnostic Slide Session 3: Case 6

A case of suspicious malignant pleomorphic xanthoastrocytoma

Etsuko Hattori¹; Yoshiki Arakawa¹; Sachiko Minamiguchi²; Masahiro Tannji¹; Youhei Mineharu¹; Hironori Haga²; Susumu Miyamoto¹

¹Department of Neurosurgery, University of Kyoto, Japan; ²Department of Diagnostic Pathology, University of Kyoto, Japan

Case: 38‐year‐old, female. She presented with headache caused by right temporal tumor 60 mm in the major axis. She underwent surgical resection of it. Although her diagnosis was PXA histopathologically, the tumor recurred at the removal cavity wall 2 months after the surgery. She underwent repeated surgery and the diagnosis was glioblastoma. Then, she was treated with Stupp protocol. After 4cycle of maintenance chemotherapy, thoracic spinal cord metastasis caused her paraplegia. She received irradiation and chemotherapy with bevacizumab and ICE. However, her intrathecal seeding of the tumor was progressing and her treatment was terminated.

Imaging findings: MRI: The lesion was hypointense on T1WI and hyperintense on T2WI. It was heterogeneous gadolinium‐enhancement. FDG‐PET: FDG uptake was high in the tumor.

Pathological findings: The sample of the first surgery was composed of spindle cells and mixed eosinophilic cells with low proliferative activity. Its diagnosis was PXA. However, the typical findings like foamy cells and degenerate structures were not observed. Endothelial proliferation and necrosis were not identified. Ki‐67 positive rate was 1%. The sample of the second surgery was composed of atypical cells with mitosis and a few GFAP/Olig2‐positive cells. Ki‐67 positive rate was 20%. There were a few pleomorphic eosinophilic cells but not remarkable. These findings resulted in the diagnosis of glioblastoma. IDH1/2, TERT, BRAF: wild type, 1p/19q codeletion (‐)

Question: Diagnosis

Case 7

TERT promoter mutation may participate in a malignant transformation of Pleomorphic xanthoastrocytoma

Junji Hosono¹; Masayuki Nitta¹; Kenta Masui²; Takashi Komori³; Hideaki Yokoo⁴; Taichi Saito¹; Takashi Maruyama¹; Yoshihiro Muragaki⁵; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ²Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan; ³Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital., Tokyo, Japan; ⁴Department of Human Pathology, Gunma University Graduate School of Medicine, Gunma, Japan; ⁵Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan

Pleomorphic xanthoastrocytoma (PXA) is categorized as a grade II other astrocytic tumours in 2016 WHO classification. Despite a relatively benign tumor, some PXAs often undergo an aggressive clinical course. The more malignant PXA is defined as anaplastic PXA (A‐PXA) now. Clinical and genetical features causing a malignant transformation have not yet become clear. Especially, typical genetic expression patterns in PXA and A‐PXA are unidentified. This is a case of PXA which caused a malignant transformation followed by acquiring TERT promoter (TERTp) mutation. A cystic mass lesion in the right temporal lobe was found on MRI scans in a 27‐year‐old woman suffered left upper quadrantanopsia and headache. 18 months after the first resection, SRS was undergone because of the first recurrence. However the tumor regrew gradually, the second operation was performed about 1year after the SRS. Afterwards, four times of recurrence were caused and five times of resection in total were undergone. At the time of the third resection, the pathological malignancy increased and the diagnosis changed from PXA to A‐PXA. In genetic analyses, TERTp mutation did not detected at the first time, but have expressed since the second surgical resection. In other words, subsequently the expression of acquired TERT promoter mutation, malignant transformation from PXA to A‐PXA was caused, and as a result, she came to repeat a recurrence many times since then. Thus, we speculated that TERT promoter mutation induced the malignant transformation and had an influence on the poor clinical outcome.

Plenary 4: PL4

Heterogeneity and complexity in Alzheimer disease

Bradley T. Hyman

Massachusetts General Hospital, Harvard Medical School

Hyman, Bradley MD PhD Alzheimer Disease Research Center Massachusetts General Hospital Boston MA USA Heterogeneity and complexity in Alzheimer Disease Introduction

The clinical rate at which patients with Alzheimer disease progress varies enormously. This heterogeneity might reflect inter‐individual differences in response to disease, in baseline cognitive reserve, and to intercurrent or concurrent pathologies. However, another possibility can be considered, that different individuals with Alzheimer disease have different strains of the disease that differ in their virulence.

Methods: We reasoned that the rate of tau propagation might uncover different strains of Alzheimer pathological changes. We used a tau bioassay to determine Tau seeding ability. Thirty two brains were examined.

Results: Cases varied in tau seeding properties by 2 fold or more. The extent of tau seeding paralleled the rank order of rates of progression of the patients, as assessed by longitudinal clinical assessments.

Discussion: Differences in Tau seeding bioactivity might reflect different strains of tau and contribute to the heterogeneity of Alzheimer disease.

Plenary 5: PL5

Neuropathology training in Japan

Mari Yoshida

Institute for Medical Science of Aging, Aichi Medical University

Currently, the definitive diagnosis of many neurological diseases remains dependent on direct examination of tissues obtained by biopsy or at autopsy. On the arrival of super‐ageing society and the increase of dementias, there is a worldwide need for well‐trained neuropathologists capable of making precise diagnoses and communicating the findings that can be widely understood. The Japanese Society of Neuropathology (JSN) was established in 1966. JSN is an interdisciplinary society with over 1200 members, consisting of neuropathologists, pathologists, neurologists, psychiatrists, psychiatrists, forensic pathologists, veterinarian, and basic neuroscientists. The Japanese Society of Pathology has a 3 or 4‐year course of training and board certification, but it does not have subspecialty of neuropathology. Therefore, there has not been specific residency or certification for neuropathology and consequently it is difficult to train young neuropathologists and resulted in decrease of the faculty of neuropathology. Members of the JSN are presently discussing improvement of the specialist system of neuropathology. The core competencies for diagnostic neuropathology includes central nervous system, muscle biopsy, peripheral nerve biopsy, and surgical pathology. We believe the existence of formal neuropathology training systems may contribute not only to diagnostic neuropathology, but also to understand structure and function of the human brain. Neuropathology trainees should realize that enormous opportunities remain for research into brain function and disease.

Symposium 31: S31‐1

Deciphering the histone code for pediatric gliomas

Cynthia Hawkins

The Hospital for Sick Children, Laboratory Medicine and Pathobiology, University of Toronto

Over the last five years next generation sequencing of pediatric high grade glioma has uncovered a plethora of information about the genetic underpinnings of this disease including the seminal discovery of novel histone H3 mutations, highlighting the importance of epigenetic alterations in this disease. Interestingly, H3.3 mutations show location‐ and age‐dependent enrichment. H3.3G34R is exclusive to hemispheric high grade glioma, most frequently in adolescents and young adults, while H3.3K27M is exclusive to the midline and is most frequent in children. In this presentation I will discuss the diagnostic and prognostic implications of histone mutations in clinical practice as well as what is known about histones as oncogenes and their mechanistic role in cancer development.

S31‐2

Whole chromosomal aberration signatures predict survival in standard‐risk non‐WNT/non‐SHH medulloblastoma: Molecular analysis of the HIT‐SIOP‐PNET4 clinical trial

Torsten Pietsch^1,2; Tobias Goschzik¹; Edward C. Schwalbe^3,4; Debbie Hicks³; Daniel Williamson³; Dominique Figarella⁵; Francois Doz⁶; Stefan Rutkowski⁷; Birgitta Lannering⁸; Steven C. Clifford³

¹Department of Neuropathology, University of Bonn, Germany; ²DGNN Brain Tumor Reference Center; ³Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; ⁴Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK; ⁵Department of Pathology and Neuropathology, Institute of Neurophysiopathology, Aix Marseille University, Marseille, France; ⁶SIREDO Cancer Center, Institut Curie and University Paris Descartes, Paris, France; ⁷University Medical Center Hamburg‐Eppendorf, Hamburg, Germany; ⁸Department of Pediatrics, University of Gothenburg and the Queen Silvia Children's Hospital, Gothenburg, Sweden

Introduction: Most children with medulloblastoma fall within the ‘standard‐risk’ clinical disease group (SR‐MB; 50‐60% of patients; 75‐85% 5‐year PFS), defined by absence of high‐risk features (e.g. metastatic disease, large‐cell/anaplastic histology, MYC amplification). Within SR‐MB, a favourable prognosis is known for WNT‐MB patients, but outcome prediction for the majority is imprecise. Novel prognostic biomarkers are urgently required to improve risk‐adapted therapies, increase survival and reduce late‐effects.

Methods: Comprehensive molecular analysis of tumour material from the pan‐European SR‐MB trial, HIT‐SIOP‐PNET4 (2001‐2006; 4‐21 years; n=136), was undertaken. WNT‐ and SHH‐MB clinical behaviour was assessed, and novel independent prognostic markers identified for SR non‐WNT/non‐SHH patients (n=91); models were validated in an independent demographically‐matched cohort (n=70).

Results: We discovered a novel whole chromosomal aberration (WCA) signature, associated with increased ploidy and multiple non‐random whole chromosome aberrations, was common in non‐WNT/non‐SHH (42% of tumours). Importantly, WCA signature‐associated biomarkers (≤2 of chr7 gain, chr8 loss and chr11 loss) predicted 100% and 98% 5‐year progression‐free survival within non‐WNT/non‐SHH patients from trial and validation cohorts, respectively. Remaining non‐WNT/non‐SHH tumours, SHH‐TP53mut and older WNT (49%), conferred significantly higher disease‐risk (5‐year PFS, 63%). Derived survival models resolved SR‐MB into favourable‐ and high‐risk groups, outperforming current risk‐stratification schemes.

Conclusions: Our molecular investigation of a contemporary SR‐MB trial has identified a widespread WCA signature in non‐WNT/non‐SHH patients, which, together with WNT (<16 years) and SHH‐TP53WT, define 51% of SR‐MB patients with 100% 5‐year PFS. WCA‐signature positive and SHH‐TP53WT patients should be urgently considered for therapy de‐escalation in future biomarker‐driven risk‐adapted clinical trials.

S31‐3

Challenges in modeling of pediatric brain tumors

Charles G. Eberhart; Eric Raabe; Ming Yuan

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA

Background: Pediatric brain tumors can be difficult to model. Challenges include limited access to tissue, slow growing tumors prone to senescence, and difficulties evaluating specific genetic drivers of neoplastic transformation and progression. We are using several approaches to address these issues.

Methods: Conditional reprogramming cell (CRC) conditions, originally developed to facilitate growth of senescence‐prone epithelial cells, are being used to culture a number of pediatric low‐grade gliomas. We are also introducing specific genetic drivers into human and murine stem cells from defined sites in the brain and spinal cord in order to generate pediatric low and high‐grade astrocytoma, ependymoma and embryonal tumors. The resulting models are being evaluated in vitro, as well as in vivo using immunocompromised mice and zebrafish.

Results: CRC conditions allow long‐term growth of a subset of previously hard to culture pediatric brain tumors, including several pilocytic astrocytoma and pleomorphic xanthoastrocytoma. These new lines have been used for preliminary preclinical testing of both established and experimental chemotherapeutic agents. Novel embryonal tumor models generated from human neural stem cells, and spinal glioma models from murine spinal progenitors, will also be described.

Conclusion: Emerging techniques can facilitate the generation of new pediatric brain tumors models useful for preclinical therapeutic and mechanistic studies.

S31‐4

Significance of molecular classification of ependymomas: C11orf95‐RELA fusion‐negative supratentorial ependymomas are a heterogeneous group of tumors

Kohei Fukuoka^1,2; Yonehiro Kanemura^3,4; Tomoko Shofuda³; Satoshi Yamashita⁵; Mai Honda‐Kitahara¹; Hitoshi Ichikawa⁶; Takashi Kohno⁷; Atsushi Sasaki⁸; Junko Hirato⁹; Takanori Hirose¹⁰; Takashi Komori¹¹; Kaishi Satomi^1,12; Akihiko Yoshida¹²; Ai Takada³; Hajime Arai¹³; Hiroaki Sakamoto¹⁴; Ryo Nishikawa²; Koichi Ichimura¹

¹Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan; ²Department of Neuro‐Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan; ³Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁴Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁵Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan; ⁶Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; ⁷Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; ⁸Department of Pathology, Saitama Medical University, Saitama, Japan; ⁹Department of Pathology, Gunma University Hospital, Maebashi, Gunma, Japan; ¹⁰Department of Diagnostic Pathology, Hyogo Cancer Center, Kobe, Hyogo, Japan; ¹¹Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ¹²Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; ¹³Department of Neurosurgery, Juntendo University, Tokyo, Japan; ¹⁴Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan

Introduction: Recent extensive molecular analyses of ependymomas unveiled that supratentorial ependymomas (ST‐EPN) are characterized by the presence of C11orf95‐RELA fusion. However, the pathogenesis of RELA fusion‐negative ependymomas remains elusive.

Materials and Methods: To validate the molecular classification of the ependymal tumors, we conducted thorough molecular analyses of 113 ependymal tumors from 107 patients within the framework of the Japan Pediatric Molecular Neuro‐Oncology Group. In this presentation, we focus on the data from 38 locally diagnosed ST‐EPNs.

Results: After central histopathological review, 9 ST‐EPNs were re‐classified as non‐ependymomas. A combination of RT‐PCR, FISH, RNA sequencing, or the DKFZ methylation classifier identified RELA fusion in 20 of 29 histologically verified ST‐EPN (68.9%). Among the 9 RELA fusion‐negative ST‐EPN, single cases of YAP1 fusion or BCOR tandem duplication were identified. In addition, a novel EP300‐BCORL1 fusion, or a FOXO1‐STK24 fusion was detected in single cases. The methylation classification identified no consistent molecular class within the 9 RELA fusion‐negative ST‐EPN or 9 re‐classified tumors. The presence of RELA fusion was not significantly associated with patients’ survival among all histologically verified ST‐EPN when a multivariate analysis using Cox regression was performed.

Conclusion: Our results indicated that RELA fusion‐negative ST‐EPNs are a heterogeneous group of tumors that are unlikely to form a single entity. Although they are histologically verified ependymomas according the WHO2016 Classification, whether those tumors belong to the same biological entity as RELA fusion‐positive ST‐EPN is questionable. Our results thus reinforce the significance of molecular classification in the diagnosis of ependymomas.

S31‐5

Foxr2 promotes formation of CNS‐embryonal tumors in a Trp53‐deficient background

Hideto Koso

Institute of Medical Science, The University of Tokyo

Embryonal tumors in the CNS are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (Foxr2) as an oncogene for medulloblastoma through a transposon‐based insertional mutagenesis screen. FOXR2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with FOXR2 activation (CNS NB‐FOXR2); however, the in vivo functions of FOXR2 remain elusive. In the present study, we analyzed the effect of Foxr2 overexpression in the mouse brain. Foxr2 and a deficiency of Trp53 promoted tumor formation in the olfactory bulb and brainstem. The tumors consisted of poorly differentiated cells that expressed neuronal and glial markers, consistent with CNS embryonal tumors. Importantly, all mice developed CNS embryonal tumors, albeit with a low incidence of medulloblastoma. The tumors were not continuous with the subventricular zone, and early proliferative lesions were observed inside the olfactory bulb and brainstem, suggesting that region‐specific progenitors are involved in tumor initiation. Tumor‐derived cells formed spheres in vitro and induced tumors that recapitulated the parental tumor upon transplantation, indicating the presence of tumor‐initiating cells. Taken together, our data demonstrate that Foxr2 plays a causative role in the formation of CNS‐embryonal tumors.

P3‐101

Preservation of staining property STAT6 immunostaining in solitary fibrous tumor/haemangiopericytoma with preoperative embolization

Hadzki Matsuda¹; Takeo Uzuka¹; Fumi Higuchi¹; Hirohisa Yajima¹; Mihoko Ishikawa³; Phyo Kim¹; Keisuke Ueki^1,2

¹Department of Neurologic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan; ²Comprehensive Cancer Center, Dokkyo Medical University Hospital, Mibu, Tochigi, Japan; ³Department of Pathology, Dokkyo Medical University Hospital, Mibu, Tochigi, Japan

We examined conditions adequate immunoreactivity of STAT6, using a specimen of solitary fibrous tumor/haemangiopericytoma (SFT/HPC) which underwent preoperative embolization.

Patient: A 26 y.o. man who had solid, irregularly shaped and well‐enhanced extraaxial tumor. Angiography and tumor embolization were perfomed followed by the resection at the same day. Intraoperative diagnosis was the SFT/HPC. Warm ischemic time from the start of embolization to complete tumor excision and immersion in 10% neutral buffered formalin was about 17hrs.

Samples: The tumor specimen were cut into about 5*10mm size and formarin‐fixed as follows: 15hrs, 39hrs (also prepared the specimens for routine path‐diagnosis), 63hrs, 87hrs, 7days, 15days, 22days.

Antibody: polyclonal anti‐STAT6(S‐20): sc‐621, 1:50, Santa Cruz, Dallas, TX.

Results: The STAT6's nuclear positivity were more distinct with short‐time‐fixed samples, but contained the area that were kept relatively good even for specimens of the longest 22‐days‐fixed. On the other hand, in the specimen of the largest diameter of tumor prepared for routine path‐exam, adequate immunopositivity were at the only within 500 mcm of the tumor surface or within 100 mcm around the relatively large blood vessel branch within the tumor. Immunoreactivity remarkably weakened inside the tumor in which formalin permeation was delayed.

Conclusion: The time‐lag from the ischemia to the formalin penetration, which affected the immunoreactivity of STAT6, was remarkable attenuation even within a relatively short period of time within 40 hours after immersion in the formalin. It might be improved by dividing the tumor before the immersion in formalin for tumors larger than 1 cm in diameter.

P3‐102

δ‐catenin modulates bevacizumab‐induced glioma invasion

Toshihiko Shimizu; Kazuhiko Kurozumi; Joji Ishida; Yoshihiro Otani; Yusuke Tomita; Yasuhiko Hattori; Atsuhito Uneda; Yuji Matsumoto; Tomotsugu Ichikawa; Isao Date

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Introduction: While bevacizumab suppresses angiogenesis, it has also been reported to cause invasive proliferation. We evaluated the effects of bevacizumab on the invasiveness of glioma cells and determined target genes involving in the regulation of bevacizumab‐induced invasion.

Material and Methods: Human glioma U87δEGFR cells were stereotactically injected into the brains of mice. Bevacizumab was administered intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology observations and mRNA was extracted from the orthotopic U87δEGFR glioma cells. Gene expression was assessed by qRT‐ PCR arrays, which included factors such as adhesion molecules. Expression of genes‐of‐interest was compared between the bevacizumab and control groups. The cytotoxicity of bevacizumab and its effect on U87δEGFR, U251MG, A172, Gli36 and its invasiveness were investigated. Expression of key factors was targeted by siRNA, and shRNA knockdown, and cell invasiveness was analyzed.

Results: In vivo, bevacizumab treatment increased glioma cell invasion. qRT‐PCR array analysis revealed upregulation of δ‐catenin (CTNND2) and several other factors. Down regulation of δ‐catenin by shRNA decreased bevacizumab‐induced glioma invasion. In vitro experiments showed that a low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased. And δ‐catenin was upregulated by a low dose of bevacizumab treatment. Silencing of δ‐catenin decreased the bevacizumab‐induced glioma invasion.

Conclusion: This study showed that some ECM factors were changed, and glioma cell invasion was induced during bevacizumab therapy. The findings suggest that δ‐catenin regulates bevacizumab‐induced glioma cell invasion, and may be a novel target for glioma treatment.

P3‐103

A case of radionecrosis, 2 years after radiation therapy

Kosuke Katayama¹; Kenichiro Asano¹; Kiyohide Kakuta¹; Akira Kurose²; Hiroki Ohkuma¹

¹Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Aomori, Japan; ²Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Aomori, Japan

Introduction: Here we report a case of radionecrosis developed 2 years after temozolomide concomitant radiation therapy for anaplastic astrocytoma.

Case: A 60 years old men was diagnosed as right frontal brain tumor, and admitted in our hospital in August 20XX. The first surgery was performed. The diagnosed was anaplastic astrocytoma (WHO 2007). After the surgery, Stupp's regimen was performed. In March 20XX+1, the tumor recurred and the second surgery was performed. Placement of BCNU wafer was performed, too. The diagnosis was anaplastic astrocytoma, IDH‐mutant (WHO 2016). Maintenance therapy was continued, however, the tumor recurred in January 20XX+3. The third surgery was performed in February.

Histological findings: Extensive geographical coagulative necrosis was found below resected lumen. In brain tissue around the lesion, astrocytosis and invasion of lymphocytes and histiocytes were observed. No tumor cell was found under the BCNU wafer. Hyaline degeneration was remarkably observed in a part of vessels. Coagulation necrosis of vessels was also observed frequently. We diagnosed this case as radionecrosis, however, IDH mutated cells existed partially.

Discussion: Radionecrosis is reported to occurs within six to fifteen months after the radiotherapy, which mimics recurrence of metastatic brain tumor or malignant glioma. We experienced a case of radionecrosis developed 2years after the radiotherapy, and thought it unlikely to be the radionecrosis. Here we report the pathological findings, clinical course and radiographical findings of this case with consideration from literatures.

P3‐104

A case of primary intracranial rhabdomyosarcoma

Maki Sakaguchi^1,2; Masashi Kinoshita¹; Katsuyoshi Miyashita¹; Shingo Tanaka¹; Hiroko Ikeda²; Takayuki Nojima²; Mitsutoshi Nakada¹

¹Department of Neurosurgery, Kanazawa University Hospital, Kanazawa, Japan; ²Department of Diagnostic Pathology, Kanazawa University, Kanazawa, Japan

Primary intracranial rhabdomyosarcoma is a very rare tumor that poses great diagnostic challenges to pathologists. We report a case of a 10‐year old female who presented with symptoms of increased intra‐cranial pressure, dressing apraxia and upper extremity paralysis secondary to recurrent hematoma formation in the left occipital area. A neoplasm was identified after the second hematoma evacuation and the primary pathologic consideration at that time was primitive neuroectodermal tumor. Initially, chemotherapy and radiotherapy were given, however, therapy subsequently shifted to more powerful chemotherapeutic agent with the confirmed diagnosis of rhabdomyosarcoma. Therapy response was noted and lasted for few years until development of recurrence. The patient had survived for 53 months from initiation of therapy. Histologically, the tumor consisted of diffuse proliferation of immature spindle cells with marked cytologic atypia and eosinophilic cytoplasm, arranged in fascicular and storiform pattern. There are frequent mitoses and scattered multi‐nucleated giant cells with eosinophilic cytoplasm. Immunohistochemically, the tumor cells show expression of skeletal muscle differentiation (myogenin, desmin, HHF35) and INI1 expression was retained. To the best of our knowledge, there are only 50 cases of primary intracranial rhabdomyosarcoma published. It is important to include rhabdomyosarcoma as a differential diagnosis when dealing a poorly differentiated tumor in the central nervous system. In this case, an accurate diagnosis of primary intra‐cranial rhabdomyosarcoma contributed to appropriate treatment and long‐term survival of a patient.

P3‐105

A case of mucinous carcinoma considered malignant transformation from intracranial germ cell tumor

Yoji Yamaguchi¹; Takashi Sasayama²; Hiroto Kajimoto²; Akiho Yamamoto³; Maki Kanzawa³; Takanori Hirose⁴; Tomoo Ito³; Eiji Kohmura²

¹Department of Neurosurgery Yodogawa Christian Hospital; ²Department of Neurosurgery Kobe University; ³Department of Diagnostic Pathology Kobe University; ⁴Department of Pathology for Regional Communication Hyogo Cancer Center

Introduction: To our best knowledge, there is no report of primary intracranial mucinous carcinoma so far.

Case: A four‐year‐old male child underwent a partial removal of a pineal tumor. Pathological diagnosis was mixed germ cell tumor including mature teratoma and choriocarcinoma. After the surgery, he received radiation therapy (whole brain and local), followed by chemotherapy up to 6 years old. Over 20 years has passed without tumor progression. However, the residual tumor growth and a hydrocephalus was recognized at the age of 27. He underwent an endoscopic third ventriculostomy (ETV) and a partial tumor removal. Pathologically, layered keratinized material with monocyte infiltration was found, however, there was no malignancy. The tumor progression was recognized about a half year later. Therefore, we diagnosed growing teratoma syndrome and performed CARE chemotherapy (carboplatin and etoposide) twice and a subtotal tumor removal. Pathological examination revealed glandular epithelium containing goblet cells with a lot of mucus. We diagnosed mucinous carcinoma.

Conclusion: If a residual tumor of germ cell tumor grows rapidly, a tumor removal should be necessary to diagnose pathologically.

P3‐106

A case of front‐temporal suprasellar papillary glioneuronal tumor

Akira Tamase¹; Osamu Tachibana¹; Sho Takata¹; Satoko Nakada²; Sohsuke Yamada²; Hideaki Iizuka¹

¹Department of Neurosurgery, Kanazawa Medical University, Uchinada, Japan; ²Department of Clinical Pathology, Kanazawa Medical University, Uchinada, Japan

Papillary glioneuronal tumors are rare tumor type, which were only recently recognized and histologically characterized by their pseudopapillary architecture associated with compact areas composed of neuronal elements in different maturation states. The authors present 16‐year‐old woman with papillary glioneuronal tumor. She was admitted to our institute because of her visual disturbance. Imaging showed a demarcated, mainly solid and cystic calcified frontal base to suprasellar extending tumor. The patient underwent surgery with bifrontal craniotomy. Histologically, it was observed pseudo‐papillary growth of GFAP positive cells and synaptophysin‐positive interpapillary collections of neurocytes. The cell nuclear fissions were not noticeable and Ki‐67 was 4.1% at the maximum site. After surgery, her visual disfunction was improved.

P3‐107

A Case of Solitary Fibrous Tumor of NAB2 Exon 6‐STAT6 Exon 17

Kodai Matsuda¹; Tsugu Hitoshi²; Tsutomu Yoshioka²; Hirata Yoko²; Kenichi Nishiyama³; Katsuyuki Hirakawa¹; Kazuki Nabeshima⁴; Touru Inoue⁵

¹Department of Neurosurgery, Fukuoka City Hospital, Fukuoka Japan; ²Department of Neurosurgery, Fukuoka Red Cross Hospital, Fukuoka Japan; ³Department of Neuropathology, Fukuoka Red Cross Hospital Fukuoka Japan; ⁴Department of Neuropathology, Faculty of Medicine, Fukuoka University Hospital, Fukuoka Japan; ⁵Department of Neurosurgery, Faculty of Medicine, Fukuoka University Hospital, Fukuoka Japan

The solitary fibrous tumor (SFT) is a relatively rare tumor among primary brain tumors. The NAB2‐STAT6 fusion gene is a driver mutation of SFT and has genetic changes similar to those of hemangiopericytoma (HPC). Recently, various NAB2‐STAT6 genotypes have been confirmed, and the relationship between genotypes and malignancy has been reported. A 49‐year‐old woman was referred to our department because of a 2‐week history of left occipital headache and nausea. Brain magnetic resonance imaging (MRI) showed a well‐demarcated and strongly enhanced mass with multi cystic compartments in the left occipital region. The mass was approximately 40 mm in diameter. A subarachnoid space was found between the tumor and the left occipital lobe, suggesting a extramedullary situated tumor. However, there was no dural tail sign. Surgical resection of the tumor was performed. The tumor was mildly elastic and hard and bleed easily. The tumor was grayish, with a clear boundary between the tumor and the brain surface. The tumor was resected sub‐totally because it had invaded into the left transverse sinus. Histological examination showed moderate cellularity with round or oval nuclei, collagenous stroma, 1 mitosis per 10 high‐power fields, and no necrotic areas. Immunohistochemical examination showed diffuse positivity for STAT 6 and CD 34. Genetic analysis showed NAB2 exon 6‐STAT6 exon 17 fusion gene. We finally diagnosed SFT.

P3‐108

Usefulness of PCR direct sequence on definitive diagnosis for chondrosarcoma: ‐two case reports‐

Taichi Shimabukuro¹; Takafumi Nishizaki¹; Makoto Ideguchi¹; Natsumi Fujii¹; Machiko Ohno¹; Norio Ikeda¹; Tokuhiro Kimura²; Eiji Ikeda²

¹The Department of Neurosurgery, Ube‐Kohsan Central Hospital, Yamaguchi, Japan; ²The Department of Pathology, Yamaguchi University Graduate School of Medicine

Introduction: Performing a differential diagnosis between chondrosarcoma (CS) and chordoma (CH) is sometimes difficult. Because CH has a poorer prognosis than CS, it is critical to perform an accurate diagnosis. We report two cases of CS where the PCR‐direct sequence proved to be useful in differential diagnoses. Case1; A 73‐year‐old woman with bilateral abducens paralyses onset. Imaging showed the heterogeneously enhanced mass lesion on MRI with destruction of clivus bones. Tumor resection under endoscope was performed by endonasal approach.

Pathological findings: Polygonal cells proliferated with reticular, funicular and solitary pattern formation in myxomas‐like extracellular matrix. Immunohistochemical staitin (IHC) showed positive for S100, but negative for AE1/AE3, CAM5.2, and EMA. The MIB1‐LI was 1%. IDH1‐R132G mutation was detected by PCR‐direct sequence, while IDH2‐R172 was wild type. Case2; A 33‐year‐old man with right trigeminal neuralgia onset. Imaging showed the ring‐like enhanced tumor bulk located in right cavernous sinus to cerebellopontine angle. Tumor resection was performed by right suboccipital craniotomy.

Pathological findings: While chondroid tissue was mainly seen, the tumor cells with palisading arrangement in myxoid stroma were partially visible. IHC was negative for AE1/AE3, CAM5.2, and EMA. The MIB1‐LI was 2%. IDH1‐R132G mutation was detected in PCR‐direct sequence, while IDH2‐R172 was wild type.

Discussion and conclusions: The IDH1 mutation was found to be common in CS and rarely so in CH, although the imaging and the pathological findings of both tumors were very similar. We conclude that PCR‐direct sequence is useful in differential diagnosis between CS and CH.

P3‐109

A Case of intraventricular giant cell glioblastoma

Tomoko Omura¹; Katsuya Umeoka¹; Toshimasa Yamada¹; Koji Adachi²; Takayuki Mizunami¹; Tsutom Hatori³; Akio Morita⁴

¹Departement of Neurosurgery, Chiba Hokuso Hospital Nippon Medical School, Chiba, Japan; ²Departement of Neurosurgery, Musashi Kosugi Hospital Nippon Medical School, Kanagawa, Japan; ³Departement of Pathology, Chiba Hokuso Hospital, Nippon Medical School, Chiba, Japan; ⁴Departement of Neurosurgery, Nippon Medical School, Tokyo, Japan

Giant cell glioblastoma (GCG) is a rare histological variant of glioblastoma(GBM). We report a case of a 60‐year‐old man who presented short‐term memory impairment. Magnetic resonance imaging(MRI) showed a well‐circumscribed mass approximately 6 cm in size, which was located within the inferior horn of the right lateral ventricle. He presented progressive left‐sided hemiparesis and impaired consciousness after admission. The patient underwent surgical removal through transcortical route 15 days after admission. Grossly, the tumor was seen as hypervascular mass with very hard consistency. Histological examination revealed pleomorphic nuclei and necrosis. Most striking feature was numerous bizarre multinucleated cells. Staining for IDH‐1 R132H, GFAP, EMA, vimentin, and S‐100 were negative in the tumor cells. Staining for p53 was positive. MGMT promoter hypermethylation and 1p/19q co‐deletion were not detected. The final pathological diagnosis was GCG. The patient underwent radiotherapy and temozolomide chemotherapy. However, MRI showed cerebellar new lesion during adjuvant therapy, which we highly suspected to be a dissemination. We performed whole brain radiotherapy and added bevacizumab. After adjuvant radiochemotherapy, a follow up MRI demonstrated decrease of enhanced lesions. Because intraventricular GCG is extremely rare, we also reviewed pertinent literature regarding this case.

P3‐110

A case of pontine glioma occurring 14 years after chemoradiotherapy of NGGCT

Takayuki Yasuda^1,2; Yoshiki Arakawa¹; Katsutsugu Umeda³; Satsuki Asai⁴; Yosuke Yamada⁴; Masahiro Tanji¹; Yohei Mineharu¹; Soichi Adachi³; Susumu Miyamoto¹

¹Department of Neurosurgery, University of Kyoto, Kyoto, Japan; ²Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ³Department of Pediatrics, University of Kyoto, Kyoto, Japan; ⁴Department of Diagnostic Pathology, University of Kyoto, Kyoto, Japan

We report a rare case of pontine glioma that occurred 14 years after chemoradiotherapy of nongerminomatous germ cell tumors (NGGCT). An 8‐year‐old girl presented with rapid reduction of visual acuity with high level of serum AFP and b‐HCG. As she had suprasellar lesion and was diagnosed as NGGCT, she underwent radiotherapy (local 26 Gy, whole ventricle 24 Gy) and chemotherapy (CPA, CDDP, VP‐16). Although the tumor was contracted without recurrence in 14 years, T2 / FLAIR high‐intense lesion on the pons appeared at the age of 22 and gradually grew with gadolinium‐enhanced portion. As methionine PET showed high accumulation in that lesion, she underwent stereotactic biopsy. Histopathological examination showed that it was composed of small round cells with round nucleus and partial high cell density similar to oligodendroglioma‐like cells. Neither microvascular proliferation nor necrosis was found. Immunohistochemical study showed positive staining for ATRX, GFAP, and Olig2, whereas negative for IDH1 R132H, MGMT, and p53 staining. The Ki‐67 labeling index was 10%. Only 1p loss was identified using FISH analysis. Therefore, it was diagnosed as low‐grade glioma, WHO grade 2. Then she received temozolomide and her enhanced‐lesion was reduced. Pontine glioma (diffuse midline glioma in WHO 2016) occurs frequently in childhood, and morphologically consisted of astrocytic component. Radiation induced glioma is rare with a high incidence in young people, but it has been reported to be no difference in genetical alterations between radiation‐induced gliomas and spontaneously occurring gliomas. We discuss the molecular analysis of this case.

P3‐111

A case of gliofibroma in adults who underwent oncogene panel test

Shunsaku Takayanagi¹; Masashi Nomura¹; Shota Tanaka¹; Masako Ikemura²; Aya Usiku²; Sinji Kohsaka³; Hiroyuki Aburatani⁴; Hiroyuki Mano³

¹Department of Neurosurgery, University of Tokyo, Tokyo, Japan; ²Department of Pathology, University of Tokyo hospital, Tokyo, Japan; ³National Cancer Center Research Institute, Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan

Introduction: gliofibroma is a tumor with glia component and mesenchymal component, and it is a very rare tumor that has only been reported to date by about 40 cases. It occurs mainly in children and is often a benign tumor. We report a case of adult patient with gliofibroma who had recurrence early postoperatively and underwent oncogene panel examination (Todai Onco Panel, TOP).

Case: A 40‐year‐old man who had no medical past history presented with repeated eye sticky seizures. In the head MRI, a contrast lesion with a diameter of 3 cm was recognized in the left temporooccipital region. The tumor was total removed by surgery. About 2 months after surgery, because nodules appeared in the removed cavity, we considered recurrence and the patient underwent radiotherapy.

Pathologic findings: Histologically, tumor cells with distinct chromatin‐deforming distortion and notches with a circular to spindle‐shaped nucleus were densely proliferated and accompanied by a desmoplastic response. Neurons and glia cells, which are thought to be non‐neoplastic, are intervened between islands. The nuclear fission image was not clear. Results of immunostaining were as follows. EMA (‐), LCA (‐), EG (‐), PFR (‐), SIGMA (‐), SIAP BRAF (‐), CD21 (‐), CD34 (‐). The MIB1 positive rate is about 7% in the high part.

Oncogene panel test result: Mutation of ARID1B was confirmed.

Discussion: Because gliofibroma is a rare disease, the characteristics of the disease are still unclear. The accumulation of cases and pathological and genetic analysis are necessary in the future.

P3‐112

Epithelioid hemangioendothelioma that metastasizes to the temporal lobe and cerebellum

Yasuzumi Matsui¹; Yoshiki Arakawa¹; Masahiro Tanji¹; Youhei Mineharu¹; Kazumichi Yoshida¹; Yasushi Takagi²; Susumu Miyamoto¹

¹The Department of Neurosurgery, University of Kyoto, Kyoto, Japan; ²The Department of Neurosurgery, University of Tokushima, Tokushima, Japan

Background: Epithelioid hemangioendothelioma is a non‐epithelial tumor derived from vascular endothelium discovered by Sharon Weiss et al. in 1975. Pathologically it shows the findings between angiosarcoma and hemangioma, but from genetically it shows different properties from both. Metastasis often occurs with a relatively slow course, and no effective treatment has been established. We report on a case of epithelioid hemangioendothelioma with intracranial metastasis.

Case: 20 year old male. An abnormal shadow was pointed out in the lung at the screening examination, and multiple examination showed multiple granular shadows in the lung. Since it was asymptomatic, three years passed and again an examination pointed out an abnormal shadow in the lung. Therefore, it was a close examination, in addition to multiple granular shadows in both lungs, multiple hepatic metastasis and cortical metastasis were observed. TBLB was performed, and diagnosis of Epithelioid hemangioendothelioma was obtained. It was introduced to our hospital for the purpose of treatment, and the head MRI revealed an expansion of the edematous change of the lesion.

Conclusion: Epithelioid hemangioendothelioma develops in the whole body, in particular occurs in lung, liver, bone, soft tissue, rarely occurs in the skull. This time, we discovered Epithelioid hemangioendothelioma on the left temporal lobe, and relapsed after 5 and 20 months. Sensitivity to radiation and chemotherapy is low from previous reports and surgical treatment should be selected for resectable cases.

P3‐113

A case of hemangioblastoma with disseminating recurrence

Yasuhide Makino¹; Yoshiki Arakawa¹

¹The Department of Neurosurgery, Kyoto University, Kyoto, Japan

Case presentation: A 41‐year‐old man presented with headache, nausea and dizziness. MRI showed a solid tumor suspecting hemangioblastoma in his left cerebellum. He underwent tumor resection and histopathological diagnosis could be hemangioblastoma but showing the similar findings of ependymoma. Three years and 11 months after the removal, MRI showed newly two lesions in his right cerebellum and a lesion in his Th2 level of thoracic spinal cord. The cerebellar lesions were removed and they were recurrent hemangioblastoma. One year later, MRI showed multiple disseminating lesions in his cerebellum and thoracic spinal cord. He received stereotactic radiotherapy in these recurrent lesions.

Discussion: Histologically, hemangioblastoma is characterized by capillary network development and stromal cell proliferation. The stromal cells have abundant cytoplasm packed with lipid vacuoles and can exhibit a clear cell‐like appearance in specimens. It has been known to be difficult to distinguish hemangioblastoma from clear cell ependymoma. The leptomeningeal dissemination of hemangioblastoma was rare. We discuss this rare case with literature consideration.

P3‐114

An elderly patient with massive dissemination diagnosed with pineal parenchymal tumor of intermediate differentiation (PPTID): An autopsy case

Kazuhiro Miyasaka¹; Ichiyou Shibahara¹; Tooru Tateoka³; Akinori Inamura¹; Masashi Akiya²; Madoka Inukai²; Makoto Saegusa²; Toshihiro Kumabe¹

¹Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; ²Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; ³Department of Neurosurgery, Yamanashi University Faculty of Medicine, Cyuo, Yamanashi, Japan

A 71‐year‐old male presented with disorientation and gait disturbance. MRI demonstrated a 13mm‐sized pineal tumor, with multiple disseminations to the lateral ventricle and the whole spinal cord. Whole‐body CT scan were negative of primary tumor. There were no definitive findings, the result of cerebrospinal fluid cytology suspected of carcinoma, thus diagnosis of brain metastases with unknown origin was made. He died of a progressive respiratory failure 3 months after the onset. The autopsy findings revealed no primary lesions in the body, and there was a 20mm‐sized tumor at the pineal body with diffuse infiltration into the surrounding brain tissue and dissemination to the ventricle wall. The tumor cells harbor high N/C ratio, a so‐called salt and pepper chromatin, and mitosis. There was also necrotic region. Immunostaining demonstrated negative AE1/AE3, and positive Synaptophysin and NCAM, thus diagnosis of PPTID was made. Pineal tumor is extremely rare accounts for below 1% of all intracranial tumors, and 21‐54% of the pineal tumor is PPTID. Furthermore, elderly PPTID patients is rare. In the present case, considering the result of cytology and old age, we diagnosed with brain metastasis with unknown origin. Due to his poor general condition, it is doubtful that we successfully provide radiation therapy, but we should have done the biopsy of pineal tumor for the early and right diagnosis. We experienced a pineal tumor with massive dissemination, which was diagnosed by an autopsy. We should keep in mind that PPTID may be the diagnosis among brain metastases of unknown origin.

P3‐115

Papillary tumor of the pineal region: Two cases report and review of the literature

Yuji Uematsu^1,2; Junya Fukai³; Kohji Fujita³; Naoyuki Nakao³

¹School of Health and Nursing Science, Wakayama Medical University, Wakayama, Japan; ²Department of Diagnostic Pathology, Wakayama Medical University Hospital, Wakayama, Japan; ³Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan

Purpose: A variety of neoplasms such as pineal parechymal cell tumors, germ cell tumors, papillary tumor of the pineal region(PTPR), and others arise in and around the pineal gland. Among them, PTPR is rare and has not been well recognized. Thus, this report describes two cases of PTPR and reviews the literature.

Methods: The first case was a 57 years‐old man who visited to examine neurolgical condition . No deficits were revealed. MRI showed a relatively high‐intensed mass on T1‐WI with homogeneous enhancement. The second case was a 68 years‐old man who was suffered from gait and memory disturbances for five months. Neurologically, cognitive decline was revealed. MRI showed a relatively low‐intensed mass with mildly heterogeneous enhancement. Both of them were totally removed through the right occipital transtentorial approach, and have not recurred for 113 and 36 months respectively.

Results: The histology both revealed the proliferation of epithelia‐like cells around the blood vessels showing papillary and solid areas. Anaplastic features such as mitosis or necrosis were only seen in the second case. The tumor cells were immunoreactive for CK, Vim., and S‐100, but not for GFAP, Olig2, EMA, NFP, SYN, and chromogranin. MIB‐1 SI was around 1.5 and 3.5% and MGMT‐immunoreactivity was moderately and highly recognized respectively. The ultrastructure of the deparffinized specimen demonstrated intermediate filaments and reminiscent junctions.

Conclusion: Rare cases of PTPR were reported and review of the literature will be discussed.

P3‐116

A case of 16 years old, right cerebellar tumor consisting of monotonous proliferating undifferentiated small cells

Takuma Oishi¹; Shouichi Deguchi²; Kouichi Mitsuya²; Nakamasa Hayashi²; Yoko Nakasu²; Takashi Sugino¹

¹Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan; ²Division of Neurosurgery, Shizuoka Cancer Center, Shizuoka, Japan

Case of A 16‐year‐old man. Right cerebellar tumor with multilocular cyst was pointed out with CT following head injury. There were no neurological deficits. Angiography didn't show tumor staining. Although PETCT had accumulation of methionine and choline, no accumulation of FDG. Undergoing craniotomy, the whole tumor was excised macroscopically. Microscopically, fragments with a maximum of 15 x 9 x 7 mm, tumor cells which had small round nucleus and eosinophilic cytoplasm with a high nuclear cytoplasm ratio, were diffuse and dense monotonous proliferating. Tumor cells lobulating by blood vessels, reactive glial cells was observed, the desmoplasia was not recognized. In the region where the spindle‐shaped cells proliferated, six mitosis appeared in one high power fields. The boundary with the brain parenchyma was clear, tumor clusters infiltrated alveolar pattern. Necrosis was not clear. Immunohistochemically, tumors showed EMA, keratin (AE1 / AE3) and desmin staining. Neurofilament Protein and NeuN stained in a small number of cells, synaptophysin weakly positive. p53 and INI1 was positive. Negative stains included GFAP, Olig 2, chromogranin A, beta‐tubulin, myogenin, IDH1. The maximal MIB 1 labeling index was 40‐50%. Glioma, medulloblastoma, AT / RT were denied. In the mesenchymal tumor, the desmoplasia was not recognized, We diagnosed of desmoplastic small round cell tumor (DSRCT). Reconfiguration of EWSR1 and WT1 was also confirmed. Up to now, there are 6 cases of intracranial DSRCT reports. Tumor cells without desmoplasia made pathological diagnosis difficult. Despite its rarity, DSRCT expands the differential diagnosis of small round cell tumors of the CNS.

P3‐117

A case of acromegaly in which a growth hormone producing pituitary adenoma recurred rapidly after administering pegvisomant

Kenichi Oyama¹; Toshio Hirohata¹; Kazuhito Yamazaki²; Shinya Miyamoto³; Katsumi Hoya³; Yasuo Ishida²; Akira Matsuno¹

¹Department of Neurosurgery / Pituitary & Endoscopic Surgery Center, Teikyo University School of Medicine, Tokyo, Japan; ²Division of Pathology, Teikyo University Chiba Medical Center, Chiba, Japan; ³Department of Neurosurgery, Teikyo University Chiba Medical Center, Chiba, Japan

Pegvisomant is a growth hormone receptor inhibitor, which suppresses serum IGF‐1 level and improves clinical symptoms of acromegaly. Here, we report a patient with acromegaly who was introduced pegvisomant in place of somatostatin receptor ligands (SRL) followed by rapid regrowth of the pituitary adenoma. The patient was a 63‐year‐old woman with treatment‐resistant diabetes mellitus, in whom acromegaly and an invasive pituitary tumor were pointed out. We performed the first trans‐sphenoidal surgery (TSS), and removed the tumor subtotally, except the tumor in the bilateral cavernous sinuses. Pathological findings showed relatively high Ki‐67 labeling index (10%). Although we had administered SRLs (octreotide and lanreotide), we had to stop them due to their side effect, flatulence. So, instead of SRLs, we introduced pegvisomant to control the disease. Two months after administering pegvisomant, a cystic tumor recurred rapidly, so the second TSS was performed. At this time, the pathological exploration showed almost same findings as that of first specimens. We restarted pegvisomant, resulting in regrowth of the tumor in seven months, and the third TSS was performed. Pathological finding showed that Ki‐67 labeling index increased from 10 % to 18 %, and p53 converted to positive. Immunostaining for somatostatin receptor showed positivity for both subtype 2 and subtype 5. As pegvisomant seemed to be related to rapid regrowth of the tumor, we stopped pegvisomant and started to use pasireotide.

P3‐118

Invasive skull base aspergillosis in a patient with lactotroph adenoma.

Yuya Nishiyama¹; Mitsuhiro Hasegawa¹; Yushi Kawazoe^1,2; Seiji Yamada³; Ryota Ito⁴; Masato Abe⁵; Yuichi Hirose¹

¹Department of Neurosurgery, Fujita Health University, Toyoake, Japan; ²Department of Comprehensive Strokology, Fujita Health University, Toyoake, Japan; ³Department of Diagnostic Pathology, Fujita Health University, Toyoake, Japan; ⁴Department of Infectious Diseases, Fujita Health University, Toyoake, Japan; ⁵Department of Pathology, School of Health Sciences, Fujita Health University, Toyoake, Japan

Aspergillosis is the most common fungal infection on the skull base, and it remains a difficult disease to diagnose and treat. We recently encountered a case of invasive aspergillosis who have lactotroph adenoma controlled by cabergoline. A 47 year‐old man had presented with nasal bleeding and diagnosed lactotroph adenoma invading the sellar floor and sphenoid sinus eleven years ago. The cabergoline treatment has been shown to be effective, and ongoing. He developed headache and visual disturbance on the left side in few weeks. MRI shows new tumor mass located medial to the optic canal. Higher doses of cabergoline was ineffective, and we therefore consider surgical resection for tumor and optic canal decompression on transsphenoidally. Although visual acuity did not recover, surgical samples show branching septate hyphae in the inflammatory granulation tissue. Antifungal agent was started immediately, Aspergillus fumigatus was identified from the culture of surgical samples subsequently. There were no significant data with brood chemical values and cerebrospinal fluid examination, therefore histopathological diagnosis is imperative in this case. We report a rare case of invasive aspergillosis presenting with lactotroph adenoma with a review of the literature.

P3‐119

A case of cavernous angioma of the optic chiasma

Kiyohide Kakuta¹; Kenichirou Asano¹; Kousuke Katayama¹; Hiroki Ohkuma¹; Akira Kurose²

¹Department of Neurosurgery, University of Hirosaki, Aomori, Japan

A 59‐years‐old male presented with angioma originating from the optic chiasma manifesting as visual disturbance. Magnestic resonance imaging relealed a heterogenous signal intensity mass at optic chiasma with a low signal intensity on T2* imaging. Right front‐temporal craniotoy was performed by the pterional approach. A subpial hematoma situated at the optic chiasm lesion. The hematoma with angiomatous component was adhere to optic chiasma, but finelly resected from srrounding structure. Histological examination of the specimens confirmed that optic chiasmal lesion was carvernous angioma. Eighteen cases of cavenous angioma of opthic nerve have been discribedand some presenting with visual disturbance. Postoperatively, his left visual aquity was slightly improved. Accoding to our case and reviews, it is the best manegiment that surgical resection with preservation of opthic nerve function.

P3‐120

IgG4 related tumor‐like or hypertrophic disease mimicking skull base meninigomas

Seiichiro Eguchi¹; Go Matsuoka¹; Kenta Masui²; Tatsuo Sawada²; Noriyuki Shibata²; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University, Tokyo Japan; ²Department of Pathology 1, Tokyo Women's Medical University School of Medicine

Subjective: IgG4 related disease (IgG4‐RD) is an entity characterized by elevated serum immunoglobulin 4 and pseudo‐tumors which contain lymphoplasmacytic infiltration of IgG4‐positve plasma cells. Lymphoplasmacyte rich meningioma and Rosai‐Dorfman disease are the differential diagnoses of the intracranial lesions related with IgG4‐RD. Here we report 2 cases of intracranial lesion of IgG4‐RD mimicking skull base meningioma.

Cases: (1) A 62‐year‐old woman underwent brain MRI because of transient global amnesia. It showed a well‐enhanced lesion enlarging along petrous bone dura and tentorium. Craniotomy was performed. There were many lymphocytes and IgG4‐positive plasmacytes histologically. Serum IgG4 was high (219 mg/dL). She was diagnosed with IgG4‐RD. (2) A 63‐year‐old woman who suffered from anosmia and underwent brain MRI. A homogenously enhanced lesion which covered anterior skull base dura, anterior falx and convexity dura was detected. Pathological diagnosis of the exenterate specimen was IgG4‐RD with bases of infiltration of IgG4‐positive lymphoplasmacytes and elevated serum IgG4.

Discussions/Conclusions: Though there have been a few cases on intracranial pseudo‐tumor related with IgG4‐RD, all cases were middle‐aged patients. The site of predilection was skull base. The lesion was homogenously well enhanced with gadolinium on MRI, like an en plaque meningiomas. But no tumor cells positive for vimentin or EMA were detected in contrast to lymphoplasmacyte rich meningiomas. Diagnostic criteria have already established and high dose steroid is effective for this disorder. It is important to suspect IgG4‐RD primarily and check the serum IgG4 if there was the finding described above on brain MRI. We have to avoid unwanted surgery.

P3‐121

A case report of a mass lesion in the brain stem positive for anti‐MOG antibodies

Kentaro Fujii¹; Kazuhiko Kurozumi¹; Toshihiko Shimizu¹; Namiko Matsumoto²; Kota Sato²; Koji Abe²; Toshiyuki Takahashi³; Kimihiko Kaneko⁴; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; ²Department of Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; ³Department of Neurology, Tohoku University School of Medicine, Sendai, and National Hospital Organization Yonezawa Hospital, Yonezawa, Japan; ⁴Department of Neurology, Tohoku University School of Medicine, and National Hospital Organization Miyagi Hospital Sendai, Japan

Background: The differential diagnosis between glioma and tumefactive demyelinating lesion (TDL) can be difficult to distinguish based on magnetic resonance imaging (MRI) findings. Here, we report a case of MOG‐antibody‐associated disease, in which the patient first received a diagnosis of TDL by biopsy, and relapsed after the treatment.

Case Presentation: A healthy 22‐year‐old man was aware of weakness in his right side and presented to a local doctor. Brain MRI revealed a lesion in the left ventral side of the medulla oblongata, so he was referred to our hospital for further examination. We considered this case as brain stem glioma according to MRI and performed a biopsy. Kluver‐Barrera staining showed extensive demyelination, and we found CD68‐positive cells at the same site. Anti‐aquaporin 4 antibody in the serum and oligoclonal band in the cerebrospinal fluid (CSF) were negative. Consequently, the pathological diagnosis was TDL. The lesion shrank after administration of steroid and we continued to observe the patient. After half a year, the patient developed generalized convulsion, and MRI revealed a scattered lesion in the right frontal lobe. He was readmitted to our hospital, and we diagnosed this case as MOG‐antibody‐associated encephalitis because MOG antibody was positive in the serum and CSF. The patient's condition improved by administration of steroid.

Conclusions: We report a case of MOG‐antibody‐associated disease that was initially misdiagnosed after the first biopsy. The definition of MOG‐antibody‐associated disease is controversial, but as preferable treatment can lead to favorable outcomes, this disease should be considered as a differential diagnosis.

P3‐122

A case report of granuloma arising from peri‐third ventricle

Koji Kondo¹; Mari Kusumi^1,2; Hitoshi Yamazaki^3,*^1,2

¹Department of Neurosurgery, Kitasato University Medical Center, Kitamoto, Japan; ²Department of Neurosurgery, Kitasato University, Sagamihara, Japan; ³Department of Pathology, Kitasato University Medical Center, Kitamoto, Japan

Presentation of Case: We document the case of 51 years old woman presented with a month of memory disturbance and apathy. The MRI imaging of brain revealed a homogenously enhancing lesion occupying peri‐third ventricle. On day five she got high fever and hyponatremia. Hypothalamic disturbance and hypopituitarism were suspected. We prescribed hydrocortisone. The tumor was biopsied with neuroendoscope. Dexamethasone was prescribed post‐operative days. And memory disturbance and apathy were recovered. And tumor was disappeared from the MRI imaging.

Pathology: Section of the brain tissue shows diffuse infiltration of an admixture of inflammatory cells including lymphoid cells and macrophages. A relatively small number of enlarged atypical cells are also infiltrated in the tissue.

Discussion: Prior steroid administration may obscure the histopathologic diagnosis.

P3‐123

Extremely delayed metastasis to the brain originated once completely cured cervical cancer of uterus

Akinori Inamura¹; Ichiyo Shibahara¹; Mitsuru Dan¹; Kazuhiro Miyasaka¹; Takuichiro Hide¹; Toshihiro Kumabe¹

¹The Department of Neurosurgery, Kitasato University, Kanagawa, Japan

Background: We experienced a rare case of a brain metastasis from cervical small cell neuroendocrine cancer (SCNEC) of uterus 13 years after the first diagnosis.

Case: 51‐year‐old female patient of disturbed consciousness was admitted. She had previous history of a surgery and adjuvant chemotherapy for cervical SCNEC 13 years before. Her annual checkup was continued for 8 years without any recurrence thus terminated 5 years before admission. Her brain MRI demonstrated a cystic tumor at the right frontal lobe which sized 6cm in diameter. An immediate surgery was done and her consciousness fully recovered. The p16 and synaptophysin immunostain were positive thus the tumor was diagnosed as a metastasis of SCNEC. CT showed no signs of uterine recurrence but an enlarged lymph node at mediastinum. The lymph node was biopsied and diagnosed as a metastasis as well. She now undergoes chemotherapy.

Discussion: SCNEC is a rare subtype of cervical cancer which accounts for 0.5‐10%. While ordinary cervical cancer rarely shows metastasis to the brain as 0.4‐2.3%, SCNEC was reported as 5 out of 15 patients had brain metastasis. The average period between the first diagnosis and metastasis to the brain was 17.2 months, however, the maximum period was reported as long as 127 months. There has not been any consensus about how long we should follow a patient.

Conclusion: We experienced a rare case of SCNEC with extremely delayed metastasis to the brain suggesting that longer period of observation is necessary. A guideline is desired for long term observation.

P3‐124

Neuropathological change after radiotherapy for HPV‐related multiphenotypic sinonasal carcinoma

Naoto Kuroda^1,2; Chikanori Inenaga²; Yuki Amano²; Hirokazu Nakatogawa²; Yoshifumi Arai³; Yoshiro Otsuki³; Tokutaro Tanaka²

¹Department of Neurosurgery, Seirei Mikatahara General Hospital, Japan; ²Department of Neurosurgery, Seirei Hamamatsu General Hospital, Japan; ³Department of Pathology, Seirei Hamamatsu General Hospital, Japan

Introduction: HPV‐related multiphenotypic sinonasal carcinoma(HMSC) is HPV‐related tumor including myoepithelial, ductal and squamous differentiation. Surgical resection with/without postoperative radiotherapy was common, however the efficacy of each treatments (surgical resection, chemotherapy and radiotherapy) were unknown. All past patients had good clinical outcome, but brain invasion wasn't reported. We treated HMSC with brain invasion by radiotherapy alone. We retrospectively discuss about effectiveness of radiotherapy from pathological findings.

Patient and method: A 69‐year‐old man with right frontal lobe intracranial hemorrhage underwent contrast MRI and it showed tumor at right frontal lobe and sinonasal tract. We performed transnasal biopsy and IMRT (40 Gy, 20 fraction). Neuroimaging study showed tumor reduction. However, he got to be coma, and died for respiratory failure at 41st day after radiotherapy. Autopsy was performed.

Result: Biopsy specimens showed immature tumor originating from epithelial and mesenchymal cell. Epithelial component consisted of basaloid cells, ductal cells and squamous differentiation. Mib‐1 index was over 30%. There were p16‐positive cells and HPV‐RNA‐ISH was partially positive. In autopsy, intranasal specimens showed necrotic changes. Therefor intracranial specimens showed same pathological findings as biopsy.

Conclusion: We performed radiotherapy alone for HMSC with intracranial invasion. This is the 1st HMSC report about the efficacy of radiotherapy comparing biopsy and autopsy pathology. Radiotherapy has some effectiveness in HMSC, especially sinonasal lesion.

Symposium 30: S30‐1

Molecular mechanisms underlying mammalian‐specific neocortical development and evolution

Tadashi Nomura¹

¹Developmental Neurobiology, Kyoto Prefectural University of Medicine

The mammalian neocortex is a conspicuous brain structure characterized by a six‐layered laminar organization. During neocortical development, excitatory projection neurons migrate toward the brain surface by changing their shapes from multi‐polar to bi‐polar morphology, which accomplishes an inside‐out pattern of cortical development. Deleterious changes in genetic and environmental factors significantly affect neuronal migration and consequence congenital cortical abnormalities. In contrast, a six‐layered neocortex does not develop in non‐mammalian species: all neurons exhibit multi‐polar shape and organize a three‐layered dorsal cortex in reptiles. However, molecular mechanisms underlying species‐specific neuronal migration and cortical organization remain unclear. Here we identify that species‐dependent regulation of Wnt signaling plays an essential role in mammalian and reptilian corticogenesis. Temporal controls of Wnt signaling in migratory neurons are crucial for multipolar‐to‐bipolar conversion in mammals, and manipulation of Wnt signaling activity phenocopied species‐specific neuronal morphologies. We suggest that heterochronic changes in Wnt activity contributed to the evolution of mammalian‐type neuronal migration and an inside‐out pattern of corticogenesis.

S30‐2

Hippocampal neurogenesis during development and aging in human

Homa Adle‐Biassette^1,2,3; Sara Cipriani²; Isidre Ferrer⁴; Eleonora Aronica⁵; Gabor Kovacs⁶; Philippe Manivet^2,3; Pierre Gressens²

¹Department of Pathology, Lariboisiere Hospital, APHP, Paris, France; ²PROTECT, INSERM, Paris Diderot University, Sorbonne Paris Cite, F‐75019 Paris, France; ³Plateforme de Bio‐Pathologie et de Technologies Innovantes en Sante, Centre de Ressources Biologiques, BB‐0033‐00064, Lariboisiere Hospital, APHP, Paris, France; ⁴Department of Pathology and Experimental Therapeutics, University of Barcelona, Bellvitge Campus; ⁵Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ⁶Institute of Neurology, Medical University of Vienna, Vienna, Austria

The main steps of the formation of the DG have been largely studied in rodents. Adult neurogenesis remains controversial in human. We characterized the progenitor subtypes, cell fate molecules and the dynamics of neurogenesis of the human hippocampal formation from the embryonic period to adulthood, including in patients with Alzheimer's disease (AD). The Ammon's horn includes two germinal compartments, the ventricular zone containing ventricular radial glial cells (RGC) and the subventricular zone containing unipolar RGC cells and TBR2‐positive intermediate progenitor cells (IPC). Pyramidal layers are generated with the “inside‐out” pattern but show differences in layer segregation between the ammonic and subicular plates. RGC density declines with neurogenesis from mid‐gestation until the perinatal period. The DG forms from two matrices. The secondary dentate matrix surrounds the dentate anlage and contains unipolar and multipolar RGC and IPC. By GW16, when the granule cell layer can be delineated, a hilar matrix and the subgranular zone (SGZ) become identifiable containing unipolar RGC and IPC. Dentate neurons are generated with the “outside‐ in” pattern. Around the perinatal period, the dense network of RGCs in the SGZ starts to decrease in density, but neurogenesis persists during childhood, few Doublecortin‐positive cells are seen in adults. The DG of both control and AD individuals shows Nestin‐positive and/or GFAP‐delta‐positive cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems minor in the adult. Supported by European Commission FP7‐ HEALTH‐2011‐2.2.2‐2/Develage

S30‐3

Normal and abnormal CNS development: new insights with fetal ultrasound

Ritsuko Kimata Pooh¹

¹CRIFM Clinical Research Institute of Fetal Medicine PMC

Fetal CNS is remarkably developing in the first trimester and changing its appearance from premature tubal structure to the bilateral cerebri, cerebellum and brainstem. Neuro‐sonoembryology has been improved with great advances of 3D ultrasound technology such as HDlive silhouette technology and studio‐live technology. However, detectable CNS abnormalities are limited in the first trimester because neuronal migration and proliferation will take place from 3rd or 4th months of gestation. From the early second trimester, the brain structure is clearly observed by ultrasound and most of congenital brain anomalies can be detected but it is quite hard to detect neuronal migration disorders during pregnancy. Phenotype of migration disorders in the cortex conspicuously appears after 28 weeks of gestation when cortical gyration/sulcation is clearly visualized. It has been believed that it is quite hard to detect migration disorder before 28 weeks. However, in most cases with neuronal migration disorder, neurological prognosis is not favorable. “Early detection of migration disorder before gyration” is one of our important missions. From our experience, early diagnoses of migration disorder have been possible by using transvaginal high‐resolution 3D ultrasound from early second trimester by observation of Sylvian fissure appearance, abnormal early sulci, irregular ventricular wall, and persistent ganglionic eminence. Close observation of those brain structural changes in detail is not generally performed however it might help to establish a new field of fetal neuroscience.

S30‐4

A continuing role for morphology in a multidisciplinary environment.

Brian Harding^1,2

¹University of Pennsylvania; ²Department of Pathology, Children's Hospital of Philadelphia

Advances in medical imaging and genetic knowledge have become so impressive of late that there is a tendency to neglect the acquisition of detailed histomorphologic information. A variety of examples taken from my personal practice, both with and without genetic diagnosis or specific imaging features, will serve to demonstrate the continuing importance of neuropathologic studies in defining new entities and formulating pathogenetic hypothesis. In the past a disorder was often first categorized in morphologic terms; but even today, neuropathologic findings may herald the emergence of a novel disorder when clinical and imaging studies are inconclusive and genetic information lacking. Reference will be made to both published and unpublished case material that reflects this situation.

Oral 15: O15‐1

Pathological characteristics and anti‐acid staining of non‐tuberculous brain infection

Jing Gao^1,2; Chenhui Mao^1,2; Hang Shen²; Jing Yuan²; Qiwen Yang³; Yi Guo⁴; Liangrui Zhou⁵; Feng Feng⁶; Fang Li⁷; Bin Peng²

¹Neurological Department Neuropathological Lab Peking Union Medical College Hospital; ²Neurologixal Department Peking Union Medical College Hospital; ³Department of Clinica Laboratory Peking Union Medical College Hospital; ⁴Neursurgical Department Peking Union Medical College Hospital; ⁵Pathological Department Peking Union Medical College Hospital; ⁶MTI Centre Peking Union Medical College Hospital; ⁷PET Centre Peking Union Medical College Hospital

Introduction: acid‐fast staining can detect Mycobacterium, actinomycetes, Legionella micdadei; some cell inclusion . We report 6 brain biopsy cases with subacute multiple intracranial infection related with acid‐fast staining.

Methods: for HE slides with inflammation, 100X microscope observation must be done. When the neutrophils were found, the Gram staining, acid‐fast staining and modified acid‐fast stain were the first choice, then PAS, silver staining, CD3, CD20, CD68 are carried out. close cooperate with microbiologist and genetic analysis.

Results: 6 cases were male 3, female 3, age 22‐44. All biopsy has neutrophils. 5 cases were diagnosed as non‐tuberculosis infection, followed up for years: 2 McMahon cocci, 2 nocardosis and 1 atypical mycobacterium. Two cases were misdiagnosed as TB for acid‐fast stain positive. Three cases were misdiagnosed as inflammatory demyelination. 4 cases of suspected pathogens were found under 100X microscope, 3 of them with gram / acid‐fast /modified acid‐fast staining positive and 1 with negative staining were confirmed as atypical mycobacterium by the culture and genetic analysis.. There were 1 TB cases without pathogen under microscope confirmed by culture. There was no significant difference between T and B cells. All the patients have no typical multinucleated giant cells. Creutzfeldt cell can be seen.

Conclusion: neutrophils in brain biopsy are an important sign of infection. The acid ‐ fast staining should be combined with GAM, modified acid‐fast satin and PAS for diagnosis differenciation. 100X is very important for the microscopic observation of brain infection. Inflammation and demyelination are also common in infectious diseases.

O15‐2

Invasive aspergillosis of paranasal sinuses with orbitocranial and brain extensive extension

Erick Gomez‐Apo¹; Alejandro Bonilla‐Mendez¹; Mario Gamez‐Rosales¹; Eric Mendoza‐Oviedo¹; Marisol Vaca‐Segura¹; Teresa Del‐Angel‐Arenas¹; Myrna Arrecillas‐Zamora¹; Rogelio Trevino‐Rangel²; Alexandro Bonifaz¹; Laura Chavez‐Macias¹

¹General Hospital of Mexico; ²Department of Microbiology, School of Medicine, UANL

Background: Chronic invasive fungal sinusitis is a rare subtype of mycotic diseases. It is characterized by a slow onset. Usually occurs in immunocompromised patients and is almost always lethal without early treatment.

Clinic Case: A forty‐two‐year‐old man. He began four months before of death with headache, decreased view, increased volume of right orbit and nose, nasal secretion, anosmia and loss of 15 pounds in a month. He continued with bilateral amaurosis, absent bilateral pupillary reflexes, purulent ocular secretion and very marked exophthalmos. Diagnosis on RMN was esthesioneuroblastoma; biopsy was taken, the diagnosis was hyalohyphomycosis (fungus ball); he was treated with Amphotericin and Voriconazole; he continued with deterioration and died.

AUTOPSY FINDINGS: The findings of autopsy were extensive destruction of orbitofrontal skeleton, ethmoid and sphenoid paranasal sinuses, with green exudate in ventral surface of frontal lobes with extension and destruction of cerebral parenchyma with abscess formation. On biopsy and autopsy, there were mycotic structures with Aspergillus features. On mycologic study, it was identified not‐pigmented fungus with very slowly‐growing in culture media. Molecular study was realized with final diagnosis of Aspegillus nidulans / Emericella nidulans infection.

Conclusion: Rhinonasal disease with intracranial extension is the commonest pattern of Aspergillus infection followed by intracranial mass lesions. Craniocerebral aspergillosis in immunocompetent hosts has three patterns of presentation that seem to correlate with clinical outcomes. Intracerebral aspergillosis is associated with the worst clinical outcome. Patients with orbital and cranial base aspergillosis had good recovery.

O15‐3

Leprosy and Buruli ulcer ‐ mycobacterial diseases with painless skin lesions

Masamichi Goto¹; Junichiro En²

¹National Sanatorium Hoshizuka‐Keiaien, Kagoshima, Japan; ²International University of Health and Welfare, Chiba, Japan

Introduction: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. M. leprae injures peripheral nerves and cause multiple mononeuropathy. Buruli ulcer is also a mycobacterial disease caused by M. ulcerans. Deep skin ulcers are formed, but curiously the ulcers are usually painless, that may lead to diagnostic delay. We compared the peripheral nerve pathology of these diseases.

Methods: Human skin biopsy specimens of leprosy and Buruli ulcer, footpads of M. leprae‐inoculated nude mice, footpads of M. ulcerans‐inoculated BALB/c mice were histologically evaluated. M. ulcerans produces toxic lipid mycolactone, thus footpads of mycolactone‐injected BALB/c mice and Schwann cell lines exposed to mycolactone were also evaluated.

Results: In the nerves of early skin lesions of human lepromatous leprosy, unmyelinated Schwann cells were the main host cells of M. leprae, and in nude mice model M. leprae were observed mainly in macrophages. In M. ulcerans‐inoculated mice, the bacilli invaded perineurium with vacuolar change of myelin sheaths. Von‐Frey sensory test showed diminished pain response [Goto, Am J Pathol 2006]. Mycolactone‐injected mice also showed similar findings [En, Infect Immun 2008]. Finally, mycolactone showed higher toxicity to cultured Schwann cells (SW10) than that to fibroblasts (L929) and macrophages (J774) [En, PLOS Negl Trop Dis 2017].

Conclusion: In leprosy, M. leprae selectively invaded Schwann cells and macrophages, but in Buruli ulcer, M. ulcerans did not show such specific tropism. As mycolactone showed high toxicity to Schwann cells, mycolactone is suggested to be responsible for the painless nature of Buruli ulcer.

O15‐4

Progression of neuropathology of Creutzfeldt‐Jakob disease and its relation to clinical findings

Yasushi Iwasaki¹; Akio Akagi¹; Maya Mimuro¹; Hiroaki Miyahara¹; Mari Yoshida¹

¹Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University

Introduction: To improve understanding of Creutzfeldt‐Jakob disease (CJD) through a clinicopathological investigation, we conducted an investigation of the clinical progression of CJD and its relation to cerebral cortical pathology.

Methods: Forty‐three cases of MM1‐type sporadic CJD were included in the study. The average age at onset was 69.7 years, and the average disease duration was 13.5 months.

Results: The earliest pathologic finding was spongiform change and the next was gliosis. Neuropil rarefaction subsequently appeared, followed by neuron loss. Based on these observations, we proposed the following stages of cerebral cortical pathology (stage I to VI): Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We found a statistically significant correlation between disease duration and stage. All diffusion‐weighted brain magnetic resonance imaging‐examined cases showed cortical hyperintensity at the time of first imaging (average of 1.6 months after onset). Myoclonus and periodic sharp‐wave complexes were first observed on electroencephalograms at an average of 2.1 months and 2.2 months, respectively, after onset. The akinetic mutism state was observed 3.2 months after onset on average.

Conclusion: The cortical hyperintensity seen on diffusion‐weighted images is a better indicator of spongiform changes than of gliosis. The first observation times of cortical hyperintensity, myoclonus, and periodic sharp‐wave complexes approximately correspond to the early phase of Stage II. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II.

Oral 16: O16‐1

Insights from biochemical analyses of regional distribution of Alzheimer's pathologies

Mitsuru Shinohara^1,2; Naoyuki Sato¹; Dennis W Dickson²; Guojun Bu²

¹National Center for Geriatrics and Gerontology, Aichi, JAPAN; ²Mayo Clinic, Jacksonville, FL, USA

Introduction: Region‐specific appearance of Alzheimer's pathologies, including Aβ and tau, has provided important clues to understand the disease pathogenesis. While region‐wide analyses were mostly done by clinical imaging studies or postmortem microscopic studies, we performed biochemical analyses through introducing in‐house ELISAs.

Methods: The amounts of Aβ, tau, apoE and other molecules related to Aβ metabolism or neurodegeneration were measured in twelve brain regions, including neocortical, limbic and subcortical areas from different stages of disease cases. We analyzed regional associations between these molecules together with difference in absolute amounts between groups.

Results: The regional distribution of full‐length Aβ, which were liable to accumulate in neocortical areas, positively associated with synaptic markers, and negatively associated with soluble apoE and an astrocytic marker, suggesting the potential involvement of synases, and apoE or astrocytes in Aβ accumulation (Shinohara et al., Acta Neuropathologica 2013). However, such associations were changed in familial Alzheimer's disease cases with mutations in APP or PSEN1, suggesting that different pathomechanism causes distinct regional Aβ accumulation (Shinohara et al., Brain 2014). N‐terminally truncated Aβ42, represented by pyroglutamylated Aβ11‐42, whose levels were increased in the symptomatic stage, were liable to accumulate in some limbic areas, and strongly associated with accumulation of tau and apoE, suggesting the critical roles of N‐terminally truncated Aβ42 in the disease progression (Shinohara et al., Brain 2017).

Conclusions: These results showed utility of our biochemical method analyzing the regional distribution of Alzheimer's pathologies to address the disease pathogenesis. Furthers studies are now underway and will be discussed.

O16‐2

The presence of Aβ toxic conformer in the inferior parietal cortex before Aβ plaque formation and its dynamic localization in aging

Yusuke Kageyama^1,4; Olga Pletnikova¹; Gay L Rudow¹; Ikuo Tooyama⁴; Kazuma Murakami⁵; Kazuhiro Irie⁵; Susan M Resnick⁶; David R Fowler⁷; Lee J Martin^1,2; Juan C Troncoso^1,3

¹Department of Pathology, The Johns Hopkins University School of Medicine; ²Department of Neuroscience, The Johns Hopkins University School of Medicine; ³Department of Neurology, The Johns Hopkins University School of Medicine; ⁴Molecular Neuroscience Research Center, Shiga University of Medical Science; ⁵Division of Food Science & Biotechnology, Graduate School of Agriculture, Kyoto University; ⁶Laboratory of Behavioral Neuroscience, NIH/NIA/IRP; ⁷Maryland Office of the Chief Medical Examiner

Introduction: Amyloid beta (Aβ) plays a critical role in the pathogenesis of amyloidopathies, notably Alzheimer's disease (AD). Solid‐state NMR analysis has identified a particular Aβ conformation which forms oligomers and is neurotoxic.

Methods: We used the 11A1 antibody that targets this toxic conformer, to examine its distribution with immunofluorescent staining in the postmortem parietal cortex of 35 human subjects, 30 to 65 years of age, found histologically free of AD lesions.

Results: 11A1 immunoreactivity was found in cortical neurons, astrocytes, neuropil and perivascular spaces at 30 years of age. Approximately 85% of neurons and 75% of protoplasmic astrocytes showed 11A1 immunoreactivity, and those proportions of neurons and astrocytes remained stable with age. 11A1 immunoreactivity was identified in nearly 30% of perivascular spaces during the fourth and fifth decades. 11A1 immunoreactivity was present in the neuropil as 1‐2 µm particles. Imaging of neuropil 11A1 immunoreactive particle with vesicle markers showed colocalization limited to CD63, which was also detected in astrocytes but not in neurons. This finding suggests that astrocytes participate in the processing of the Aβ toxic conformer. Notably, in the sixth decade, at the same time that the proportion of perivascular spaces with 11A1 immunoreactivity declines to approximately 20%, the number of neuropil 11A1 immunoreactive particles sharply increased.

Conclusion: The Aβ toxic conformer is present in various cell types and brain structure in the inferior parietal cortex. Around age 50 years, this steady state of Aβ changes with a decrease of perivascular Aβ and a concomitant increase in neuropil Aβ.

O16‐3

Sushi repeat‐containing protein 1 co‐accumulates with cerebrovascular Abeta deposits in cerebral amyloid angiopathy

Yasuteru Inoue¹; Mitsuharu Ueda¹; Masayoshi Tasaki¹; Akari Takeshima²; Yohei Misumi¹; Takayuki Kosaka¹; Taro Yamashita¹; Hitoshi Takahashi²; Akiyoshi Kakita²; Yukio Ando¹

¹Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ²Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

Introduction: Sporadic cerebral amyloid angiopathy (CAA)is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhage and dementia. Several molecules have reportedly co‐accumulated with tissue amyloid deposits in patients with amyloidosis. The exact molecules that co‐accumulate with cerebrovascular Aβ deposits are still not fully known. Here, to identify the key molecules in CAA diagnosis and pathogenesis that may lead to therapy for CAA, we used laser capture microdissection to perform proteomic analyses with cerebral blood vessels.

Methods: We performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and determined the levels of highly expressed proteins in cerebral blood vessels in CAA.

Results: We focused on sushi repeat‐containing protein 1 (SRPX1), which is specifically expressed in CAA‐affected cerebral blood vessels. Immunohistochemical studies revealed that SRPX1 co‐accumulated with Aβ deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co‐accumulated with Aβ deposits in senile plaques. Furthermore, we demonstrated that both Aβ40 and Aβ42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aβ40. Knockdown of SRPX1, in contrast, reduced the formation of Aβ40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells.

Conclusion: SRPX1 may be a novel molecule that is up‐regulated in cerebrovascular Aβ deposits and that may increase Aβ‐induced cerebrovascular degeneration in CAA.

O16‐4

Sex and age interact to determine clinicopathologic differences in Alzheimer's disease

Amanda M. Liesinger¹; Neill R. Graff‐Radford²; Ranjan Duara³; Kelly M. Hinkle¹; Fadi S. Hanna Al‐Shaikh¹; Sarah K. DiLello¹; McKenna F. Johnson¹; Dennis W. Dickson¹; Melissa E. Murray¹

¹Neuroscience Department, Mayo Clinic, Jacksonville, FL; ²Neurology Department, Mayo Clinic, Jacksonville, FL; ³Wein Center for Alzheimer's Disease and Memory disorders, Mount Sinai Medical Center, Miami Beach, FL

Women reportedly make up two‐thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi‐Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53‐102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and med did not differ. Men were younger at age onset, had a shorter disease duration, and more often had atypical (non‐amnestic) clinical presentations. The frequency of autopsy‐confirmed AD among women and men stratified by age at death revealed an inverse U‐shaped curve in men and a U‐shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional densities of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of tangle density compared to men, especially in the hippocampus. Men and woman did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically confirmed AD has the same frequency in women and men, but their clinical presentations ages at onset tend to differ.

Asian Diagnostic Slide Session 1: Case 2

A Pediatric Case of Left Frontal Hemorrhagic Tumor Radiographically Diagnosed as Leukoencephalopathy with Calcification and Cysts

Ryuta Saito¹; Masayuki Kanamori¹; Mitsugu Uematsu²; Mika Watanabe³; Teiji Tominaga¹

¹Department of Neurosurgery, Tohoku University Graduate School of Medicine; ²Department of Pediatrics, Tohoku University Hospital; ³Division of Pathology, Tohoku University Hospital

Introduction: Leukoencephalopathy with calcifications and cysts (LCC) is a rare disease in which parenchymal cysts and calcifications within a widespread leukoencephalopathy can cause a broad spectrum of neurological symptoms. It is now recognized as a cerebral microangiopathy caused by mutations in SNORD118.

Case: 9 year‐old boy developed a sudden onset of generalized seizure and admitted to local hospital. MRI demonstrated blurring of corticomedullary junction at left frontal cortex and spotty T2 high intensity at left basal ganglia. As he had an episode of infection 1 month prior to disease onset, acute disseminated encephalomyelitis was suspected. Anti‐epileptic treatment was given at this time. Half an year later, he developed headache, anorexia, and vomiting. MRI obtained at this point revealed multicystic hemorrhagic mass with perifocal edema at his left frontal lobe. CT scan revealed calcification. Opthalmological examination revealed no abnormalities. With the radiological diagnosis of LCC, he was referred to pediatric department for genetic examinations of SNORD118 mutation, which turned out to be negative. After then, the lesion enlarged with multi‐stage hemorrhage and was subjected to surgical removal. Histological examination of removed mass revealed multicystic, calcified lesion with hemosiderosis and gliosis. Fibrinoid degeneration and hyalinization of the vascular wall was also found.

Discussion: The pathological diagnosis given for this case was microangiopathy. Though LCC was suspected, SNORD118 mutation was negative. We would like to ask for discussion regarding the final diagnosis.

Case 1

Oligodendroglioma, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation of a 31‐year‐old male: A case report and literature review

Yangki Minn¹; Seonghye Choi²; Se Hoon Kim³; Yoon Jin Cha⁴

¹Department of Neurology, Hallym Univeristy College of Medicine, Kangnam Sacred Heart Hospital, Seoul, Korea; ²Department of Neurology, Inha University College of Medicine, Inha Hospital, Incheon, Korea; ³Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea; ⁴Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea

Introduction: Oligodendroglioma (OLG) is a diffusely infiltrating glial neoplasm. Sporadic case reports of neuronal differentiation of OLG and subset of neuronal gene expression of OLGs have been identified. Here, we report a rare case of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation in a 31‐year‐old male patient.

Clinical summary: A 31‐year‐old male patient without specific medical history was admitted with a seizure. Brain computed tomography revealed 7cm‐sized contrast enhancing cystic mass with internal necrosis and calcification, in the right frontal lobe. With suspicion of anaplastic OLG, gross total removal of the tumor was performed. Patient is alive well after subsequent radiotherapy.

Pathologic findings: On microscopic examination, diffusely infiltrating tumor cells with clear cytoplasm were found in the cortex. Necrosis or endovascular proliferation was not found. Majority of tumor was composed of OLG‐like clear tumor cells with chicken‐wire pattern vasculatures. Throughout the tumor, atypical gangliocyte‐like cells having hyperchromatic nulcei, prominent nucleoli and ample cytoplasm were observed. Differential diagnoses included ganglioneuronal tumors and OLG with gangliocytic differentiation. Tumor cells were diffusely positive for OLIG2 and IDH (R132H) immunohistochemical stainings (IHC). Scattered ganglion‐like cells were highlighted by NeuN and synaptophysin IHC. Subsequent fluorescence in situ hybridization analysis revealed 1p/19q codeletion, confirmed the diagnosis of OLG, IDH‐mutant and 1p/19q‐codeleted with gangliocytic differentiation.

Conclusion: Although rarely found, OLG can have neuronal differentiation and may present like long‐term epilepsy associated tumor and lead to underdiagnosis. IDH analysis, preferentially IDH1 IHC would help to discriminate OLG from other glioneuronal tumors.

Oral 17: O17‐1

Possible distinction of four repeat tau‐positive lesions of Alzheimer's disease and progressive supranuclear palsy probed by four repeat‐specific antibodies.

Momoko Ebashi^1,4; Miho Uematsu¹; Ayako Nakamura¹; Yoshinori Ito²; Katsuiku Hirokawa³; Satoshi Kamei⁴; Toshiki Uchihara¹

¹Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science; ²Yokuhukai Hospital; ³Nitobe Memorial Nakano General Hospital; ⁴Division of Neurology, Department of Medicine, Nihon University School of Medicine

Introduction: Accumulation of abnormal tau protein is the pathological hallmark shared between Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Their distinction is based on the distribution of tau‐positive neurons, associated cytopathology or tau isoforms. It is generally believed that 4 repeat (4R)‐tau lesions in AD and PSP are not readily distinguishable. In this study, we tried to distinguish immunorepresentation of 4R‐tau through comparison between two different antibodies toward 4R‐tau.

Methods: Thirteen autopsied brains (4 AD, 4 PSP and 5 AD+PSP) were enrolled in this study. 4R‐tau immunoreactivity probed either by polyclonal anti 4R‐tau® or monoclonal RD4® was compared in each case, and evaluated the structural characteristic of 4R‐tau.

Result: The anti 4R‐tau® labeled a larger number of AD‐neurofibrillary tangles (NFTs) more intensely than RD4®. This difference was evident in AD‐prone areas such as hippocampus and locus ceruleus (LC) that of RD4®, which is particularly highlighted in the hippocampus and LC in all 13 cases. In contrast, RD4® labeled a larger number of tuft‐shaped astrocytes (TAs) more intensely than anti 4R ‐tau®. This preferential immunoreactivity of RD4® on TA over anti 4R‐tau® was evident in PSP‐prone regions such as the precentral gyrus and brainstem tegmentum even if AD and PSP pathologies are coexistent, while NFT in PSP cases exhibited equivalent immunoreactivity to anti 4R‐tau® and RD4®.

Conclusion: Preferential RD4® immunoreactivity on TA/PSP is in contrast with complementary preference of anti 4R‐tau® on NFT/AD. This may provide a clue to clarify difference in molecular species of 4R‐tau between AD and PSP.

O17‐2

TDP‐43 pathology contributes to clinicopathological heterogeneity of corticobasal degeneration

Shunsuke Koga¹; Kouri Naomi²; Ronald L. Walton¹; Keith A. Josephs³; Neill Graff‐Radford⁴; Ryan J. Uitti⁴; Jay A. van Gerpen⁴; Zbigniew K. Wszolek⁴; Owen A. Ross¹; Dennis W. Dickson¹

¹Department of Neuroscience, Mayo Clinic; ²Department of Pathology, Boston Children's Hospital; ³Department of Neurology (Behavioural Neurology & Movement Disorders); ⁴Department of Neurology, Mayo Clinic

Introduction: Corticobasal degeneration (CBD) is a clinicopathologically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to examine whether transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology contributes to clinicopathologic heterogeneity of CBD.

Methods: Paraffin‐embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy‐confirmed CBD cases were screened with immunohistochemistry for phospho‐TDP‐43. In cases having TDP‐43 pathology, additional brain regions were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP‐43 pathology, and clinicopathologic and genetic features were compared between the clusters.

Results: TDP‐43 pathology was observed in 45% of CBD cases, most frequently in the midbrain tegmentum (80% of TDP‐43‐positive cases), followed by the subthalamic nucleus (69%). TDP‐43‐positive CBD was divided into TDP‐limited (52%) and TDP‐severe (48%) groups by hierarchical clustering analysis. TDP‐severe patients were more likely clinically diagnosed with PSP than TDP‐limited and TDP‐negative patients because of high frequency of downgaze palsy. Multivariable logistic regression model revealed that TDP‐43 pathology in the midbrain tectum was strongly associated with the downgaze palsy. In addition, tau burden in olivopontocerebellar structures was significantly greater in TDP‐43‐positive than TDP‐43‐negative CBD cases. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP‐severe (65%) than in TDP‐negative (89%) and TDP‐limited (91%) CBD cases.

Conclusion: TDP‐severe CBD is a distinct clinicopathologic subtype of CBD, which presents with PSP‐like presentations. Severe tau pathology in olivopontocerebellar structures may associate with this subtype.

O17‐3

Morphological features of neuronal and glial tau pathology in GGT (Types II and III)

Hidetomo Tanaka¹; Yasuko Toyoshima¹; Shinobu Kawakatsu²; Takeshi Miura^3,4; Takeshi Ikeuchi³; Osamu Onodera⁴; Hitoshi Takahashi¹; Akiyoshi Kakita¹

¹Department of Pathology, Brain Research Institute, Niigata University; ²Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University; ³Department of Molecular Genetics, Brain Research Institute, Niigata University; ⁴Department of Neurology, Brain Research Institute, Niigata University

Introduction: Globular glial tauopathy (GGT) is a new 4‐repeat tauopathy characterized pathologically by globular glial inclusions (GGIs), namely those affecting oligodendrocytes (GOIs) and astrocytes (GAIs). GGT is classified into three pathological subtypes (Types I, II and III), but the morphological features of the individual subtypes have not been investigated in detail. We have previously reported unique neuronal cytoplasmic inclusions (NCIs) in GGT Type III, but the morphological features of these NCIs are not included in the GGT consensus recommendations (Ahmed et al., 2013). Here, we investigated the morphological differences between the GGT subtypes, focusing on NCIs and GAIs.

Methods: We investigated the tau pathology in 5 cases of GGT (Type II, n = 2; Type III, n = 3) in terms of the immunohistochemistry, biochemistry, 3D structure, ultrastructure, and quantity of the tau‐positive inclusions.

Results: GAIs in Type II were large with radiating process‐like structures, whereas those in Type III were small with perikaryal large globular structures. 3D morphometric analysis supported the above findings. NCIs showed three unique subgroups in terms of shape: 1) diffusely granular, 2) thick and cord‐like, and 3) round and horseshoe‐shaped. Thick cord‐like NCIs were a feature in both types. Interestingly, the round/horseshoe‐shaped NCIs were observed only in Type III.

Conclusions: The present findings suggest that morphological differences among GAIs may be a new feature to support classification of the subtypes, and that the presence of characteristic NCIs is a new common feature of GGT.

O17‐4

Sequential distribution patterns of aging‐related tau astrogliopathy (ARTAG) in the human brain

Gabor G. Kovacs^1,2; Sharon X. Xie³; John L. Robinson²; Edward B. Lee²; Douglas H. Smith⁴; Theresa Schuck²; Virginia M.‐Y. Lee²; John Q. Trojanowski²

¹Institute of Neurology, Medical University of Vienna, Vienna, Austria; ²Center for Neurodegenerative Disease Research (CNDR), Institute on Aging and Department of Pathology & Laboratory Medicine; ³Department of Biostatistics and Epidemiology; ⁴Department of Neurosurgery, Center for Brain Injury and Repair, the Perelman School of Medicine (PSOM) at the University of Pennsylvania, Philadelphia, PA, USA

Introduction: Aging‐related tau astrogliopathy (ARTAG) describes tau pathology in astrocytes in different locations and anatomical regions. In the present study we addressed the question of whether sequential distribution patterns can be recognized for ARTAG.

Methods: By evaluating 687 postmortem brains with diverse disorders we identified ARTAG in 455. We evaluated frequencies and hierarchical clustering of anatomical involvement and used mathematical and statistical approaches to model the sequential distribution of ARTAG and astroglial tau pathologies across different brain regions.

Results: For subpial and white matter ARTAG we recognize three and two patterns, respectively, each with two stages initiated or ending in the amygdala. Subependymal ARTAG does not show a clear sequential pattern. For grey matter (GM) ARTAG we recognize a striatal pathway of spreading bidirectionally towards the cortex and/or amygdala, or the brainstem and an amygdala pathway, which precedes the involvement of the striatum and proceeds bidirectional spread towards the cortex or the brainstem.

Conclusion: Tau‐astrogliopathy type‐specific sequential patterns require the consideration of complex relationships of various tau pathologies and therefore cannot be simplified as neuron‐based staging systems alone.

Oral 18: O18‐1

Autopsy on home‐cared patients with neurological disorders. Nitobe model to improve patient care, medical education and research

Toshiki Uchihara¹; Shuta Toru¹; Michio Yamane²; Hiroshi Shintaku^3,4; Masanobu Kitagawa⁴; Katsuiku Hirokawa³; Tetsuya Irie²

¹Neurology, Nitobe Memorial Nakano General Hospital; ²Internal Medicine, Nitobe Memorial Nakano General Hospital; ³Pathology, Nitobe Memorial Nakano General Hospital; ⁴Pathology, Tokyo Medical and Dental University

Introduction: Decline in the rate and number of autopsy is accelerating in all countries. Cost‐conscious management of patients further accelerates this decline. Because increasing number of patients are cared for outside of hospital such as home or institutions for chronic care, autopsy on these individuals deceased outside of hospital may counteract this decline.

Method: Nitobe model to support autopsy on these patients was constructed based on financial supports by several private grants. This Nitobe model includes autopsy units (Nitobe Memorial Hospital and Tokyo Medical and Dental University Hospital) and a support center to afford the cost for autopsy (3,000 USD/autopsy) and transport of the deceased.

Results: Among 31 patients autopsied in this project, 3 deceased at home and 28 deceased at hospital after 2.1 yr (mean) of home care. This cohort included 9 ALS, 8DLB, 4PSP, 3AD, 2MyD, MSA, CBD, pure autonomic failure, leukoencephalopathy and cerebral hemorrhage. Some of the home care physicians became interested in examining the autopsy samples by themselves and in presenting the data in CPC or even in this meeting. Some of the patients’ family or even patients themselves gave consent for autopsy during life.

Conclusion: Autopsy on the deceased at home is a feasible strategy that can improve the quality of care. Increasing the number of autopsy may strengthen the scientific basis for medical education and research. Public financial support is indispensable to expand this Nitobe model so that similar system is available all over Japan or in the world.

O18‐2

Introducing the Digital Brain Tumor Atlas (DBTA), a freely available repository for brain tumor whole slide scans

Thomas Roetzer^1,2; Anna‐Christina Moser^1,2; Petra Mercea^2,3; Romana Prihoda^2,3; Baran Atli^1,2; Johannes A. Hainfellner^1,2; Bernhard Baumann⁴; Georg Langs⁵; Adelheid Woehrer^1,2

¹Institute of Neurology, Medical University of Vienna, Vienna, Austria; ²Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; ³Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; ⁴Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; ⁵Computational Imaging Research Lab, Department of Biomedical Imaging and Image‐guided Therapy, Medical University of Vienna, Vienna, Austria

Introduction: Digital pathology is increasingly recognized as useful tool for precision diagnostics. Typical tasks include tissue segmentation, disease classification, and enhanced prognostic rating. Yet, the underlying machine learning algorithms depend on the availability of large, freely available datasets for training. However, there are only few whole slide image (WSI) repositories available online, and those do not cover all brain tumor types in sufficient quality and quantity.

Methods: Herein, we introduce the Digital Brain Tumor Atlas, which will comprise all brain tumor entities according to the current WHO classification. Using MedUni Vienna's neurobiobank as resource, we are in the process of scanning a total of 10,000 expert‐selected H&E slides in high resolution using a Hamamatsu NanoZoomer XR scanner. All slides will be published online together with basic clinical annotations.

Results: So far, we have digitized roughly 2,500 WSI covering 100 different brain tumor types. In parallel, information on gender, location, and age has been collected for all cases. For a subset of 500 glioma cases, we have further manually segmented tumor, necrotic and hemorrhagic areas.

Conclusions: We introduce the Digital Brain Tumor Atlas, a freely available online repository for H&E slide scans of all brain tumor entities. The atlas will fill a critical gap and prove valuable 1. for training machine learning algorithms for enhanced diagnostics 2. as a training tool for young neuropathologists, and 3. as an independent, external validation dataset for digital pathology projects.

O18‐3

Allied neurosurgical results World War I and II

John Hedley‐Whyte¹

¹Sheridan Professorship, Harvard University

Introduction: In 1941 Major, later Sir Benjamin Rycroft was teaching me to read. I asked “Why do the eye cases come to you while the neurosurgical cases are flown to Oxford?” “Neurosurgery is harder than the eye business. They are flown with catheters draining their spinal fluid.” “Why?” “So they do not burst their brains.” “Who thought that up?” “Cushing in Boston. He trained all the head doctors: Cairns at Oxford, Ross at Barts.”

Methods: Harvard, Yale, Oxford and U.S. Library of Congress Archives and other sources were examined.

Results: In World War I Allied mortality from head injury was reduced from 37% to 20% after King George V in 1915 gave Harvey Cushing de facto control. His pupil, Sir Hugh Cairns, halved it to 10% in WWII. His transport protocol remains a modern standard of care, but required 10,000 DC3s, C47s, Dakotas and UK and US Nurse Air Nightingales and 130 Air Landing Strips, newly constructed in Europe alone. The Allied World War I and II Medical and Surgical Services were under the control of Presidents Wilson and FD Roosevelt and Kings George V and VI.

Conclusion: Cushing's 3‐volume biography of Sir William Osler won a Pulitzer Prize. The Cushings were married from the Regius and Lady Osler's Oxford home. Before the Cushings’ honeymoon it was arranged that President Teddy Roosevelt would give the Romanes Lecture on June 7, 1910 at Oxford University. Friendly relations with Japan were espoused.

O18‐4

In order to keep neuropathology succession, teaching stuffs of neuropathology should deal with neuroanatomy, clinical clerkship, and clinical office for outpatients, as well as neuropathology

Shinsuke Kato¹; Shinichiro Kitao¹; Masahiro Ii¹; Hiroshi Kohama¹; Kosuke Yonekura¹; Yuki Kaida¹; Norihisa Itaki¹; Junko Yasui¹; Kana Oda¹; Keiko Kato¹

¹Division of Neuropathology, Tottori University Faculty of Medicine

Introduction: Our Neuropathology Division has expanded the field of clinical and practical medicine dealing with patients in addition to basic medical sciences, since we founded a neuropathology clinical office for outpatients in Tottori University in 2013.

Methods: With respect to the education of the basic medicine, we have succeeded for students to learn smoothly neuropathology by our lecturing neuroanatomy. Regarding the education of the clinical medicine, in order to bring up the sixth‐year medical students to be the physicians who want to major in neuropathology in the future, we educate outpatient clinic as one part of clinical clerkship. Around 2‐4 third‐year students study neuropathology during one month as Laboratory Assignment System (LAS).

Results: As for the neuroanatomy, we deliver 20 hour‐Lecture, perform 12 hour‐BrainCutting practice, and instruct 3 hour‐Tissue Observation training. Referring the neuropathology, 13 hour‐Lecture and 15 hour‐Tissue Observation training are carried out. Concerning the clinical clerkship, we teach the autopsy and surgical neuropathology as a routine. When we conduct an outpatient clinic, we make clinical‐clerkship students attend the clinic with patients and physicians, and have them learn pathologic findings. Synchronously, we make these students understand that the patients are able to receive pathology services of high quality through the clinic. As excellent results of LAS, one student published English paper and one student passed USMLE Step1.

Conclusion: In order to keep the succession to neuropathology in Medical University, it is necessary that neuropathologists deal with neuroanatomy, neuropathology, clinical clerkship, and outpatient clinic as high‐quality diagnostic services.

Asian Diagnostic Slide Session 2: Case 3

Diffuse leptomeningeal glioneuronal tumor exhibiting 1p/19q co‐deletion and H3F3K27M mutation: A rare case with unique molecular profile

Kavneet Kaur¹; Aruna Nambirajan¹; Prit Benny Malgulwar¹; Vaishali Suri¹; Mehar Chand Sharma¹; Ajay Garg¹; Chitra Sarkar¹

¹Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi

Introduction: Diffuse leptomeningeal glioneuronal tumour is a new entity in the recent WHO classification of CNS tumors (2016). It is a rare tumour characterised by predominant and widespread involvement of leptomeninges with olidodendroglial like cytology. Most are low grade, a small proportion show aggressive behaviour. Hence, a definite WHO grade is not yet assigned.

Clinical Summary: A 13‐year‐old female child presented with complaints of diminution of vision in both the eyes and headache for 1 year and paraplegia with bladder and bowel dysfunction for 1 month. MRI revealed an intadural extramedullary mass in D1‐D4 region of spinal cord and multiple T2 hyperintense lesions in sulcal spaces of cerebellum, choroid plexus of lateral ventricles, putamina and pons.

Pathological findings: Biopsy from a mass in the conus region showed a tumour with oligodendroglia like cytology and glomeruloid vessls with moderately high MIB1 index. The tumour cells were immunopositive for GFAP, synaptophysin, NeuN while negative for IDH and showed retained ATRX expression. The tumor was found to harbour 1p/19q co‐deletion by Fluorescence in‐situ hybridisation and H3F3A mutation by Sanger‐sequencing. IDH mutations and BRAF alterations were not found by sequencing and RT‐PCR, respectively. Based on overall findings, a diagnosis of diffuse leptomeningeal glioneuronal tumour was rendered.

Conclusions: Diffuse leptomeningeal glioneuronal tumors represent a distinct clinico‐pathological entity. Even though histologically benign, they can show aggressive behavior due to involvement of wide area of leptomeninges, development around the brainstem and difficulty in surgical intervention. Hence, a knowledge of this new entity is imperative to arrive at the correct diagnosis.

Case 4

38‐year‐old female with right parietal lobe mass lesion

Yue‐Shan Piao¹; Zhuo Li¹; Lei‐Ming Wang¹; Dan‐Dan Wang¹; Yong‐Juan Fu¹; De‐Hong Lu¹

¹Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Beijing, China 100053

A 38‐year‐old female began to show paroxysmal left‐sided numbness more than 5 months ago. Her symptom spontaneously relieved after 1‐2 minutes each time,without physical weakness and hallucinations. No disturbance of consciousness, nausea and vomiting. The patient felt uncomfortable before each attack, but it cannot be clearly stated. The patient visited orthopedics over 3 months ago. Cervical MRI showed no obvious abnormality. Then, the examination of head CT taken 11 days ago indicated a low density in the right basal ganglia, parietal lobe and temporal lobe, which was considered as space‐occupying lesion. A cranial MRI showed a right parietal lobe mass lesion, being likely low‐grade glioma.

The patient was admitted to the department of neurosurgery and the tumor was completely removed under the microscope (5cm×4cm×3cm).

Histopathologically, there is low grade diffuse glioma with infiltration to the cortex, showing both astrocytic and oligodendrocytic differenciations. A few mitosis but no necrosis and vascular prolifration were noted. Immunohistochemically, the tumor cells were positive for GFAP, olig2, IDH1R132H and overexpression of p53 (60%), but negative for ATRX. The ki‐67 index was about 10%. PCR‐based direct sequencing determined the mutation of IDH1(R132H) and wild type of TERT promoter. FISH revealed 1p and 19q codeletion.

Morphological diagnosis of mixed oligoastrocytoma, WHO grade II was made. But, we couldn't make the integrated diagnosis according the revised version of the WHO classification of tumors of the central nervous system (2016 edition).

Our case suggested that there was a true “oligoastrocytoma” with both molecular features of astrocytoma and oligodendroglioma.

Case 5

A case of pediatric high grade glioneuronal tumor, NEC

Jiro Akimoto¹; Nobuyuki Nakajima¹; Norio Ichimasu¹; Michihiro Kohno¹; Yukiko Shishido‐Hara²; Jun Matsubayashi²; Toshitaka Nagao²; Sumito Nobusawa³; Junko Hirato³; Hideaki Yokoo³

¹Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan; ²Department of Human Pathology, Tokyo Medical University, Tokyo, Japan; ³Department of Patholofy, Graduate School of Medicine, Gunma Univeristy, Gunma, Japan

A 7‐year‐old girl presented with 4 months history of gradually worsening headache and nausea. On admission, she presented with left hemiparesis. CT and MRI demonstrated a large right temporo‐parietal cystic tumor with mural nodule, which was strongly enhanced by Gd‐DTPA. Our pre‐operative diagnosis was pilocytic astrocytoma or pleomorphic xanthoastrocytoma, and underwent 2‐stage total resection of the nodule and cyst wall of the tumor was undertaken. The tumor consisted of three histopathological components (A‐C). Part (A) displayed proliferation of pleomorphic astrocytes with moderate cellularity with high mitotic index. Microvascular proliferation and micro‐necrosis were also seen. Part (B) showed dense proliferation of small tumor cells with scant cytoplasm, presenting biphasic patterns. Part (C) included small tumor cells with neuronal differentiation on neuropil‐like matrix. Part (A) was immuno‐positive for GFAP, S100 and Olig‐2, and negative for IDH‐1 and neuronal markers. In contrast, Part (C) was negative for GFAP and positive for neuronal markers. Ki‐67 labeling index was 60‐70% in Part (A), but minimum in Part (B) and (C). Molecular analysis demonstrated only CDKN2A/B homozygous deletion, without IDH1/BRAF/H2F3A/FGFR1/ TERT promoter mutations. According to these histological findings, post‐operative 54Gy / 30Fr extended focal irradiation was undertaken, and her symptoms were gradually improved. Our integrated diagnosis of this case is a pediatric high grade glioneuronal tumor, NEC. Discussion about the histo‐pathological diagnosis of this rare tumor is requested.

Asian Diagnostic Slide Session 3: Case 6

A case of suspicious malignant pleomorphic xanthoastrocytoma

Etsuko Hattori¹; Yoshiki Arakawa¹; Sachiko Minamiguchi²; Masahiro Tannji¹; Youhei Mineharu¹; Hironori Haga²; Susumu Miyamoto¹

¹Department of Neurosurgery, University of Kyoto, Japan; ²Department of Diagnostic Pathology, University of Kyoto, Japan

Case: 38‐year‐old, female. She presented with headache caused by right temporal tumor 60 mm in the major axis. She underwent surgical resection of it. Although her diagnosis was PXA histopathologically, the tumor recurred at the removal cavity wall 2 months after the surgery. She underwent repeated surgery and the diagnosis was glioblastoma. Then, she was treated with Stupp protocol. After 4cycle of maintenance chemotherapy, thoracic spinal cord metastasis caused her paraplegia. She received irradiation and chemotherapy with bevacizumab and ICE. However, her intrathecal seeding of the tumor was progressing and her treatment was terminated.

Imaging findings: MRI: The lesion was hypointense on T1WI and hyperintense on T2WI. It was heterogeneous gadolinium‐enhancement. FDG‐PET: FDG uptake was high in the tumor.

Pathological findings: The sample of the first surgery was composed of spindle cells and mixed eosinophilic cells with low proliferative activity. Its diagnosis was PXA. However, the typical findings like foamy cells and degenerate structures were not observed. Endothelial proliferation and necrosis were not identified. Ki‐67 positive rate was 1%. The sample of the second surgery was composed of atypical cells with mitosis and a few GFAP/Olig2‐positive cells. Ki‐67 positive rate was 20%. There were a few pleomorphic eosinophilic cells but not remarkable. These findings resulted in the diagnosis of glioblastoma. IDH1/2, TERT, BRAF: wild type, 1p/19q codeletion (‐) Question: Diagnosis.

Case 7

TERT promoter mutation may participate in a malignant transformation of Pleomorphic xanthoastrocytoma

Junji Hosono¹; Masayuki Nitta¹; Kenta Masui²; Takashi Komori³; Hideaki Yokoo⁴; Taichi Saito¹; Takashi Maruyama¹; Yoshihiro Muragaki⁵; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ²Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan; ³Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital., Tokyo, Japan; ⁴Department of Human Pathology, Gunma University Graduate School of Medicine, Gunma, Japan

Pleomorphic xanthoastrocytoma (PXA) is categorized as a grade II other astrocytic tumours in 2016 WHO classification. Despite a relatively benign tumor, some PXAs often undergo an aggressive clinical course. The more malignant PXA is defined as anaplastic PXA (A‐PXA) now. Clinical and genetical features causing a malignant transformation have not yet become clear. Especially, typical genetic expression patterns in PXA and A‐PXA are unidentified. This is a case of PXA which caused a malignant transformation followed by acquiring TERT promoter (TERTp) mutation. A cystic mass lesion in the right temporal lobe was found on MRI scans in a 27‐year‐old woman suffered left upper quadrantanopsia and headache. 18 months after the first resection, SRS was undergone because of the first recurrence. However the tumor regrew gradually, the second operation was performed about 1year after the SRS. Afterwards, four times of recurrence were caused and five times of resection in total were undergone. At the time of the third resection, the pathological malignancy increased and the diagnosis changed from PXA to A‐PXA. In genetic analyses, TERTp mutation did not detected at the first time, but have expressed since the second surgical resection. In other words, subsequently the expression of acquired TERT promoter mutation, malignant transformation from PXA to A‐PXA was caused, and as a result, she came to repeat a recurrence many times since then. Thus, we speculated that TERT promoter mutation induced the malignant transformation and had an influence on the poor clinical outcome.

Plenary 4: PL4

Heterogeneity and complexity in Alzheimer disease

Bradley Hyman¹

¹Massachusetts General Hospital, Harvard Medical School

Hyman, Bradley MD PhD Alzheimer Disease Research Center Massachusetts General Hospital Boston MA USA Heterogeneity and complexity in Alzheimer Disease Introduction: The clinical rate at which patients with Alzheimer disease progress varies enormously. This heterogeneity might reflect inter‐individual differences in response to disease, in baseline cognitive reserve, and to intercurrent or concurrent pathologies. However, another possibility can be considered, that different individuals with Alzheimer disease have different strains of the disease that differ in their virulence. Methods: We reasoned that the rate of tau propagation might uncover different strains of Alzheimer pathological changes. We used a tau bioassay to determine Tau seeding ability. Thirty two brains were examined. Results: Cases varied in tau seeding properties by 2 fold or more. The extent of tau seeding paralleled the rank order of rates of progression of the patients, as assessed by longitudinal clinical assessments. Discussion: Differences in Tau seeding bioactivity might reflect different strains of tau and contribute to the heterogeneity of Alzheimer disease.

Plenary 5: PL5

Neuropathology training in Japan

Mari Yoshida¹

¹Institute for Medical Science of Aging, Aichi Medical University

Currently, the definitive diagnosis of many neurological diseases remains dependent on direct examination of tissues obtained by biopsy or at autopsy. On the arrival of super‐ageing society and the increase of dementias, there is a worldwide need for well‐trained neuropathologists capable of making precise diagnoses and communicating the findings that can be widely understood. The Japanese Society of Neuropathology (JSN) was established in 1966. JSN is an interdisciplinary society with over 1200 members, consisting of neuropathologists, pathologists, neurologists, psychiatrists, psychiatrists, forensic pathologists, veterinarian, and basic neuroscientists. The Japanese Society of Pathology has a 3 or 4‐year course of training and board certification, but it does not have subspecialty of neuropathology. Therefore, there has not been specific residency or certification for neuropathology and consequently it is difficult to train young neuropathologists and resulted in decrease of the faculty of neuropathology. Members of the JSN are presently discussing improvement of the specialist system of neuropathology. The core competencies for diagnostic neuropathology includes central nervous system, muscle biopsy, peripheral nerve biopsy, and surgical pathology. We believe the existence of formal neuropathology training systems may contribute not only to diagnostic neuropathology, but also to understand structure and function of the human brain. Neuropathology trainees should realize that enormous opportunities remain for research into brain function and disease.

Symposium 31: S31‐1

Deciphering the histone code for pediatric gliomas

Cynthia Hawkins¹

¹The Hospital for Sick Children

Over the last five years next generation sequencing of pediatric high grade glioma has uncovered a plethora of information about the genetic underpinnings of this disease including the seminal discovery of novel histone H3 mutations, highlighting the importance of epigenetic alterations in this disease. Interestingly, H3.3 mutations show location‐ and age‐dependent enrichment. H3.3G34R is exclusive to hemispheric high grade glioma, most frequently in adolescents and young adults, while H3.3K27M is exclusive to the midline and is most frequent in children. In this presentation I will discuss the diagnostic and prognostic implications of histone mutations in clinical practice as well as what is known about histones as oncogenes and their mechanistic role in cancer development.

S31‐2

Whole chromosomal aberration signatures predict survival in standard‐risk non‐WNT/non‐SHH medulloblastoma: Molecular analysis of the HIT‐SIOP‐PNET4 clinical trial

Torsten Pietsch^1,2; Tobias Goschzik¹; Edward C. Schwalbe^3,4; Debbie Hicks³; Daniel Williamson³; Dominique Figarella⁵; Francois Doz⁶; Stefan Rutkowski⁷; Birgitta Lannering⁸; Steven C. Clifford³

¹Department of Neuropathology, University of Bonn, Germany; ²DGNN Brain Tumor Reference Center; ³Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; ⁴Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK; ⁵Department of Pathology and Neuropathology, Institute of Neurophysiopathology, Aix Marseille University, Marseille, France; ⁶SIREDO Cancer Center, Institut Curie and University Paris Descartes, Paris, France; ⁷University Medical Center Hamburg‐Eppendorf, Hamburg, Germany; ⁸Department of Pediatrics, University of Gothenburg and the Queen Silvia Children's Hospital, Gothenburg, Sweden

Introduction: Most children with medulloblastoma fall within the ‘standard‐risk’ clinical disease group (SR‐MB; 50‐60% of patients; 75‐85% 5‐year PFS), defined by absence of high‐risk features (e.g. metastatic disease, large‐cell/anaplastic histology, MYC amplification). Within SR‐MB, a favourable prognosis is known for WNT‐MB patients, but outcome prediction for the majority is imprecise. Novel prognostic biomarkers are urgently required to improve risk‐adapted therapies, increase survival and reduce late‐effects.

Methods: Comprehensive molecular analysis of tumour material from the pan‐European SR‐MB trial, HIT‐SIOP‐PNET4 (2001‐2006; 4‐21 years; n=136), was undertaken. WNT‐ and SHH‐MB clinical behaviour was assessed, and novel independent prognostic markers identified for SR non‐WNT/non‐SHH patients (n=91); models were validated in an independent demographically‐matched cohort (n=70).

Results: We discovered a novel whole chromosomal aberration (WCA) signature, associated with increased ploidy and multiple non‐random whole chromosome aberrations, was common in non‐WNT/non‐SHH (42% of tumours). Importantly, WCA signature‐associated biomarkers (≤2 of chr7 gain, chr8 loss and chr11 loss) predicted 100% and 98% 5‐year progression‐free survival within non‐WNT/non‐SHH patients from trial and validation cohorts, respectively. Remaining non‐WNT/non‐SHH tumours, SHH‐TP53mut and older WNT (49%), conferred significantly higher disease‐risk (5‐year PFS, 63%). Derived survival models resolved SR‐MB into favourable‐ and high‐risk groups, outperforming current risk‐stratification schemes.

Conclusions: Our molecular investigation of a contemporary SR‐MB trial has identified a widespread WCA signature in non‐WNT/non‐SHH patients, which, together with WNT (<16 years) and SHH‐TP53WT, define 51% of SR‐MB patients with 100% 5‐year PFS. WCA‐signature positive and SHH‐TP53WT patients should be urgently considered for therapy de‐escalation in future biomarker‐driven risk‐adapted clinical trials.

S31‐3

Challenges in modeling pediatric brain tumors

Charles G. Eberhart; Eric Raabe; Ming Yuan

Department of Pathology, John Hopkins University School of Medicine, Baltimore, USA

Background: Pediatric brain tumors can be difficult to model. Challenges include limited access to tissue, slow growing tumors prone to senescence, and difficulties evaluating specific genetic drivers of neoplastic transformation and progression. We are using several approaches to address these issues.

Methods: Conditional reprogramming cell (CRC) conditions, originally developed to facilitate growth of senescence‐prone epithelial cells, are being used to culture a number of pediatric low‐grade gliomas. We are also introducing specific genetic drivers into human and murine stem cells from defined sites in the brain and spinal cord in order to generate pediatric low and high‐grade astrocytoma, ependymoma and embryonal tumors. The resulting models are being evaluated in vitro, as well as in vivo using immunocompromised mice and zebrafish.

Results: CRC conditions allow long‐term growth of a subset of previously hard to culture pediatric brain tumors, including several pilocytic astrocytoma and pleomorphic xanthoastrocytoma. These new lines have been used for preliminary preclinical testing of both established and experimental chemotherapeutic agents. Novel embryonal tumor models generated from human neural stem cells, and spinal glioma models from murine spinal progenitors, will also be described.

Conclusion: Emerging techniques can facilitate the generation of new pediatric brain tumors models useful for preclinical therapeutic and mechanistic studies.

S31‐4

Significance of molecular classification of ependymomas: C11orf95‐RELA fusion‐negative supratentorial ependymomas are a heterogeneous group of tumors

Kohei Fukuoka^1,2; Yonehiro Kanemura^3,4; Tomoko Shofuda³; Satoshi Yamashita⁵; Mai Honda‐Kitahara¹; Hitoshi Ichikawa⁶; Takashi Kohno⁷; Atsushi Sasaki⁸; Junko Hirato⁹; Takanori Hirose¹⁰; Takashi Komori¹¹; Kaishi Satomi^1,12; Akihiko Yoshida¹²; Ai Takada³; Hajime Arai¹³; Hiroaki Sakamoto¹⁴; Ryo Nishikawa²; Koichi Ichimura¹

¹Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan; ²Department of Neuro‐Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan; ³Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁴Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁵Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan; ⁶Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; ⁷Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; ⁸Department of Pathology, Saitama Medical University, Saitama, Japan; ⁹Department of Pathology, Gunma University Hospital, Maebashi, Gunma, Japan; ¹⁰Department of Diagnostic Pathology, Hyogo Cancer Center, Kobe, Hyogo, Japan; ¹¹Department of Laboratory Medicine and Pathology ^{Neuropathology}, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; ¹²Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; ¹³Department of Neurosurgery, Juntendo University, Tokyo, Japan; ¹⁴Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan

Introduction: Recent extensive molecular analyses of ependymomas unveiled that supratentorial ependymomas (ST‐EPN) are characterized by the presence of C11orf95‐RELA fusion. However, the pathogenesis of RELA fusion‐negative ependymomas remains elusive.

Materials and Methods: To validate the molecular classification of the ependymal tumors, we conducted thorough molecular analyses of 113 ependymal tumors from 107 patients within the framework of the Japan Pediatric Molecular Neuro‐Oncology Group. In this presentation, we focus on the data from 38 locally diagnosed ST‐EPNs.

Results: After central histopathological review, 9 ST‐EPNs were re‐classified as non‐ependymomas. A combination of RT‐PCR, FISH, RNA sequencing, or the DKFZ methylation classifier identified RELA fusion in 20 of 29 histologically verified ST‐EPN (68.9%). Among the 9 RELA fusion‐negative ST‐EPN, single cases of YAP1 fusion or BCOR tandem duplication were identified. In addition, a novel EP300‐BCORL1 fusion, or a FOXO1‐STK24 fusion was detected in single cases. The methylation classification identified no consistent molecular class within the 9 RELA fusion‐negative ST‐EPN or 9 re‐classified tumors. The presence of RELA fusion was not significantly associated with patients’ survival among all histologically verified ST‐EPN when a multivariate analysis using Cox regression was performed.

Conclusion: Our results indicated that RELA fusion‐negative ST‐EPNs are a heterogeneous group of tumors that are unlikely to form a single entity. Although they are histologically verified ependymomas according the WHO 2016 Classification, whether those tumors belong to the same biological entity as RELA fusion‐positive ST‐EPN is questionable. Our results thus reinforce the significance of molecular classification in the diagnosis of ependymomas.

S31‐5

Foxr2 promotes formation of CNS‐embryonal tumors in a Trp53‐deficient background

Hideto Koso

Institute of Medical Science, The University of Tokyo

Embryonal tumors in the CNS are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (Foxr2) as an oncogene for medulloblastoma through a transposon‐based insertional mutagenesis screen. FOXR2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with FOXR2 activation (CNS NB‐FOXR2); however, the in vivo functions of FOXR2 remain elusive. In the present study, we analyzed the effect of Foxr2 overexpression in the mouse brain. Foxr2 and a deficiency of Trp53 promoted tumor formation in the olfactory bulb and brainstem. The tumors consisted of poorly differentiated cells that expressed neuronal and glial markers, consistent with CNS embryonal tumors. Importantly, all mice developed CNS embryonal tumors, albeit with a low incidence of medulloblastoma. The tumors were not continuous with the subventricular zone, and early proliferative lesions were observed inside the olfactory bulb and brainstem, suggesting that region‐specific progenitors are involved in tumor initiation. Tumor‐derived cells formed spheres in vitro and induced tumors that recapitulated the parental tumor upon transplantation, indicating the presence of tumor‐initiating cells. Taken together, our data demonstrate that Foxr2 plays a causative role in the formation of CNS‐embryonal tumors.

Significance of lineage analysis in recurrent gliomas; a case study of tumor “missing” IDH1 mutation

Toru Umehara¹; Hideyuki Arita¹; Naoki Kagawa¹; Yasunori Fujimoto¹; Yonehiro Kanemura^2,3; Haruhiko Kishima¹

¹Departments of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan; ²Department of Biomedical Research and Innovation Research, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ³Kansai Molecular Diagnosis Network for CNS Tumors, Japan

Introduction: Recent comprehensive genomic analysis of initial and recurrent tumor has revealed that glioma cells evolve through selection of specific clones for survival under therapies. The recurrent glioma is essentially a regrowing or re‐emerging tumor consisting of the common parental clones with the initial tumor, and it should be distinguished from de novo tumor emerging from other clones. Here, we describe a pair of gliomas showing different genetic profiles including IDH status at the time of initial and recurrence.

Case Report: A 36‐year‐old male developed a left frontal lobe tumor and underwent a craniotomy for gross total resection. The histological diagnosis was glioblastoma (based on CNS WHO2007), and the tumor was positive for IDH1 R132H mutant protein. He was treated with chemoradiation after the surgery. The tumor locally recurred at the ventral area of excised cavity 68 months after the initial surgery. The recurrent tumor was resected and diagnosed as glioblastoma, IDH‐wild type. Genetic analysis revealed the initial tumor harbored IDH1 and TERT mutations and 1p/19q codeletion while the recurrent tumor presented whole arm 1p deletion without 19q deletion or IDH and TERT mutations. Microarray analysis showed few chromosomal copy number changes were shared in the paired samples.

Discussion and Conclusion: The present case showed the recurrent tumor had different genetic profile from that of initial tumor, and it could be regarded as a de novo or a radiation‐induced glioblastoma. The discrimination between recurrent and de novo tumor is crucial for the management of clinically “recurrent” gliomas.

Clinical and pathological characteristics of elderly patients with lower‐grade gliomas: a multi‐institutional retrospective study in Kansai Molecular Diagnosis Network for CNS Tumors

Junya Fukai¹; Yoshinori Kodama^2,3; Takanori Hirose^2,4; Yuji Uematsu^1,2; Naoyuki Nakao^1,2; Tomoko Shofuda^2,5; Daisuke Kanematsu^2,5; Ema Yoshioka^2,5; Kanji Mori^2,6; Yonehiro Kanemura^2,5

¹Department of Neurological Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan; ²Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, Japan; ³Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; ⁴Department of Diagnostic Pathology, Hyogo Cancer Center, Hyogo, Japan; ⁵Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁶Department of Neurosurgery, Kansai Rosai Hospital, Hyogo, Japan

Background: Elderly patients with diffuse gliomas are increasing in number and their prognoses are potentially poor. For better understanding of ‘elderly glioma’, we conducted a multi‐institutional retrospective study of elderly cases enrolled in Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network). In this study, we focused on the current state of clinical practice and molecular analysis for the lower‐grade gliomas (LrGG).

Methods: We collected elderly cases (70 years and older) diagnosed with diffuse gliomas in Kansai Network. All cases underwent central pathology review and integrated diagnosis was made based on the 2016 WHO Classification. We analyzed clinical and pathological characteristics of WHO grade II & III cases.

Results: Included in the study were 26 elderly patients (WHO grade II: 7, III: 19), median age was 75 years. The cohort consisted of 17 astrocytic and 9 oligodendroglial tumors. IDH1/2 was wild‐type in 18 tumors (69%), 1p/19q codeletion was detected in 7 tumors and TERT promoter was mutated in 14 of 25 tumors (56%). MGMT promoter was methylated in 16 tumors (62%). According to the combined IDH/TERT classification, the cohort was divided as follows: IDHmut/TERTmut, 6; IDHmut/TERTwt, 2; IDHwt/TERTwt, 8; IDHwt/TERTmut; 9. Median progression‐free survival and overall survival times of grade II/III cases were 12.3/14.7 and 20.5/29.7 months, respectively.

Discussion and Conclusions: Lower‐grade astrocytomas might rarely have IDH1/2 mutation in the elderly. The prognosis of elderly patients with LrGG including oligodendroglial tumors might be poorer than that of non‐elderly. Further validation in a larger cohort is warranted.

Clinical and immunohistochemical analysis of H3.3 K27M antibody positive glioma

Fumiyuki Yamasaki¹; Takeshi Takayasu¹; Motoki Takano¹; Ushio Yonezawa¹; Vishwa J. Amatya³; Masako Yoshihiro¹; Yukio Takeshima³; Kazuhiko Sugiyama²; Kaoru Kurisu¹; Vega Karlowee¹

¹Department of Neurosurgery, Hiroshima University Hospital, Hiroshima, Japan; ²Department of Clinical Oncology & Neuro‐oncology Program, Hiroshima University Hospital, Hiroshima, Japan; ³Department of Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, it leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation positive tumors, and revealed the association of high EZH2 expression with poor survival. Our study included 12 patients, with age ranged of 6 to 56 years, treated between 2007 and 2016. All patients underwent preoperative MRI study including non‐enhanced T1WI, T2WI, FLAIR, DWI, and gadolinium‐enhanced T1WI. Immunohistochemical staining was performed againts H3K27M, H3K27me3, EZH2, mutant isocitrate dehydrogenase 1 (mIDH1), alpha‐thalassemia X‐linked intellectual disability (ATRX), p53 and MIB1 antibodies. The result revealed that all patients were negative for IDH1‐R132H and H3K27me3, with H3K27M positive. Staining against EZH2 was negative in all histological features of grade II (3 of 12 cases) and positive in grade III and IV ones. The median overall survival of EZH2 positive tumor was significantly sorter than that of EZH2 negative tumor (P = 0.0082, 14.5 months vs. 28.4 months). Retained ATRX staining was found in mostly grade III and IV (6 of 12 cases). P53 was predominantly positive in astrocytoma and glioblastoma. Intratumoral hemorrhage is the most important characteristics of H3K27M mutant positive thalamic glioma, and observed in 44.4% (4 of 9 patients) of thalamic tumor. We suggest that the expression of EZH2 is increases in the poor prognosis patient with H3K27M‐mutant diffuse midline glioma. Further studies are necessary to understand the mechanism.

Gene mutations and prognosis in midline glioma

Yasuhiko Hattori¹; Kazuhiko Kurozumi¹; Kentaro Fuji¹; Toshihiko Shimizu¹; Yusuke Tomita¹; Atsuhito Uneda¹; Yuji Matsumoto¹; Nobushige Tsuboi¹; Hiroyuki Yanai²; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ²Department of Pathology, Okayama University Hospital, Okayama, Japan

Introduction: Midline gliomas are aggressive brain malignancies with poor prognosis. They are considered WHO grade IV tumors, regardless of histologic features. Because they are usually difficult to resect, they are generally treated with radiation with or without chemotherapy. Here, we evaluated gene mutation effects on midline glioma outcomes.

Methods: We assessed patient background, tumor location, histological diagnosis, and treatment progress in 27 patients who underwent surgery and were diagnosed with midline gliomas from 2000 to 2018.

Results: The 27 patients included 17 males and 10 females, with a median age at surgery of 36 years (range: 5–75 years), and tumors located at the thalamus (n = 15), midbrain (n = 5), pons (n = 3), medulla oblongata (n = 2), and thoracic spinal cord (n = 2). All patients underwent biopsy or resection. Histologic diagnoses were pilocytic astrocytoma (n = 5), diffuse astrocytoma (n = 2), anaplastic astrocytoma (n = 14), and glioblastoma (n = 4). The H3F3AK27M mutation was present in 11 patients. Twenty‐four patients were treated with radiation; 17 patients received temozolomide and 4 received bevacizumab. Median overall survival was 20 months (high‐grade gliomas: 20 months; low‐grade gliomas: 49.5 months; K27M⁺ group: 18 months; K27M⁻ group: 29 months). A few cases, complicated by hydrocephalus, underwent endoscopic third ventriculostomy or Ommaya reservoir implantation.

Conclusion: Midline gliomas with H3F3AK27M tend to have poor prognosis. Their optimal treatment is based on many factors, such as histologic and genomic findings, clinical course, and quality of life.

Evaluation of survival and pathology of midline glioma in the WHO 2016 classification

Takahiro Yamaguchi¹; Ryuhei Kitai¹; Yoshifumi Higashino¹; Hiroshi Arai¹; Kenzo Tsunetoshi¹; Ken Matsuda¹; Hidetaka Arishima¹; Toshiaki Kodera¹; Ken‐ichiro Kikuta¹; Yoshiaki Imamura²

¹Department of Neurosurgery, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; ²Unversity of Fukui Hospital, Division of Surgical Pathology, Fukui, Japan

Introduction: In WHO 2016 classification, midline glioma is classified into WHO grade IV when including H3 K27M mutation. We re‐classified our midline gliomas diagnosed based on WHO 2007 by H3 K27M mutation, and evaluated pathology and overall survival (OS).

Method: 23 midline gliomas, glioblastoma (GBM) 9, anaplastic astrocytoma (AA) 8, diffuse astrocytoma (DA) 5, high grade glioma (HGG) 1 were re‐classified by immunochemical method.

Result: 23 cases reclassified into diffuse midline glioma, K27M‐mutant (K27M‐Mut) 7 (GBM 2, AA 3, DA 1, HGG 1), and midline glioma, K27M‐wildtype (K27M‐Wt) 16 (GBM 7, AA 5, DA 4). Age in K27M‐Mut was significantly lower than that in K27M‐Wt (median: 12 years old vs 61.5 years old, p = 0.011). Pathologically, small round cells with low nuclear atypia increased in K27M‐Mut. Immunohistochemically, IDH1 R132H, MGMT were negative, ATRX was loss, and Nestin was positive in all case of K27M‐Mut. IDH1 R132H was positive in 4 (25%), MGMT was positive in 5 (31%), loss of ATRX was 8 (67%), and Nestin was positive in 14 (88%) in K27M‐Mut. There was no significant differences in OS between K27M‐Mut and K27M‐Wt.

Conclusion: There was no significant differences in OS between K27M‐Mut and K27M‐Wt in midline gliomas. Diffuse midline glioma, H3 K27M‐mutant had some characteristic findings in immunohistochemically.

Clinicopathological role in malignant glioma with leucine‐rich alpha‐2 glycoprotein

Takuya Furuta^1,2; Satoru Komaki¹; Yasuo Sugita¹; Hemragul Sabit²; Masanori Tachikawa³; Sumio Ohtsuki⁴; Tetsuya Terasaki³; Mitsutoshi Nakada²

¹Department of Pathology, Kurume University, Kurume, Japan; ²Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan; ³Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; ⁴Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

Background: Leucine‐rich α‐2 glycoprotein (LRG1), one of the proteins we have extracted as a candidate blood biomarker for glioblastoma, is produced in hepatocytes in response to acute inflammation such as bacterial infection. LRG1 is secreted into the blood and involved in angiogenesis in malignant tumors. Clinicopathological significance of LRG1 in malignant glioma was analyzed.

Method: Consecutive 92 ases pathologically diagnosed as glioma (astrocytoma, oligodendroglioma, glioblastoma) in Kurume University from January 2012 to April 2018 (IDH‐mutant (IDH ‐mut) 37 cases, IDH‐wildtype (IDH‐wt) 55 cases), and 6 cases with IDH mutation treated in Kanazawa University Hospital from April 2001 to May 2016, whose tumors showed malignant transformation. Biological characteristics as a diagnostic marker or prognostic marker of glioblastoma were examined by immunohistochemistry of LRG1.

Results: LRG1 was expressed in the cytoplasm of tumor cells. In IDH‐wt glioblastoma, the positive rate of LRG1 was significantly higher (65.5% vs 16.2%, p < 0.0001) compared to IDH‐mut astrocytoma and oligodendroglioma. All IDH‐mut astrocytomas including glioblastomas showed negative for LRG1. Although statistically significant difference was not obtained, LRG1 expression group in IDH‐wt glioblastoma showed a favorable prognosis compared with the LRG1 negative group.

Conclusinos: LRG1 is promising as a diagnostic marker for IDH‐wt glioblastoma, suggesting the possibility of being associated with the presence or absence of IDH mutation.

Is main route of glioma invasion through perivascular space?

Ryuhei Kitai; Takahiro Yamauchi; Tomochika Hashimoto; Katsuhide Tai; Ken‐ichiro Kikuta; Kazufumi Sato

Department of Neurosurgery, University of Fukui, Japan

The invasive ability of gliomas has been focused that Scherer categorised neural and glial cells or alongside the white matter tracts, blood vessels and meninges. Recently, glioma implantation experiment showed rapid invasion along to the blood vessels. The main route of the invasion was reconsidered by using immunohisstochemical staining for individual tumor cells. Materials and Method. Our archival 6 specimens were used, especially the surrounding brain tissue were well preserved. The diagnosis was Diffuse midline glioma, Anaplastic Oligodendroglioma IDH‐1 mut, Glioblastoma IDH‐Mut, one autopsy case is included. The immunohistochemical staining for K27N and IDH‐1 R132H showed the individual tumor cell itself obviously. More than 50 vessels in adjacent brain tissue were observed. the vascular guided infiltration was defined as the tumor cell was attached vascular wall and the tumor cells exist in perivascular space during tissue fixation. Result, the vessels of vascular guided invasion were 9.75% + ‐6.9%. The main invaded cells were along the nerve fiber. The longitudinal vessels also observed that only few tumor cells were existed, but main a little percentage. In conclusion, the invasion was occurred along with nerve fiber.

MGMT methylation cutoff value in quantitative analysis related to prognosis of newly diagnosed glioblastoma

Jun‐ichi Adachi; Mitsuaki Shirahata; Tomonari Suzuki; Kazuhiko Mishima; Atsushi Sasaki²; Ryo Nishikawa

Department of Neurosurgery/NeuroOncology, Saitama Medical University International Medical Center

Background

MGMT promoter methylation is an important biomarker related to glioblastoma therapeutic reactivity and prognosis. There are qualitative and quantitative methods as assays for MGMT methylation. Although the qualitative method is common, there is a disadvantage that low or high methylation can not be distinguished. The quantitative method is an excellent method for evaluating methylation of tumors characterized by intratumoral heterogeneity like malignant glioma, but cutoff value of methylation that defines prognosis is unknown. Therefore, we examined the cutoff value of quantitative MGMT methylation assay determining prognosis in glioblastoma.

Methods: 180 newly diagnosed glioblastoma which underwent radiotherapy and temozolomide treatment after tumor removal in our department were included. MGMT methylation was quantitatively analyzed by methylation‐specific high resolution melting (MS‐HRM) analysis. For each level of methylation, progression‐free survival (PFS) and overall survival (OS) were calculated and statistically analyzed.

Results: In the low MGMT methylation cases in which the proportion of methylation was 25% or less in PFS and 30% or less in OS, no difference was observed in PFS and OS as compared with those of unmethylated cases. The cutoff value of MGMT methylation contributing most to survival was calculated to be 35% by the survival classification and regression tree method.

Conclusion: It is difficult to predict the prognosis in MGMT hypomethylated glioblastoma, and methylation analysis by quantitative analysis is important. In the quantitative MS‐HRM method, we found that the value of MGMT methylation of 35% is useful as a cut off determining the prognosis of glioblastoma.

Usefulness of intraoperative molecular diagnosis of glioma using real‐time PCR

Shunichi Koriyama^1,2,3; Masayuki Nitta¹; Kenta Masui⁵; Takashi Maruyama^1,2; Taiichi Saito¹; Takashi Komori^4,5; Yoshihiro Muragaki^1,2; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ²Faculty of Advanced Techno‐Surgery, Institute of Advanced Biomedical Engineering & Science , Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan; ³Medical Corp. JOJINKAI Ushiku Aiwa General Hospital, Ibaraki, Japan; ⁴Laboratory of Brain Tumor Pathology, Department of Brain Development and Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; ⁵Department of Pathology 1, Tokyo Women's Medical University, Tokyo, Japan

Background: Based on the comprehensive gene association studies in recent years, the revision was issued in 2016 WHO classification, integrating genetic information in glioma diagnosis. Many studies have been reported the correlation between each molecular subtype and prognosis in the new classification. Gliomas surgery is required to maximum tumor resection with functional preservation. Currently, our institute decides a surgical strategy based on the morphological diagnosis and genetic information from the obtained tissue during the operation. We evaluated the IDH 1/2 gene mutations and 1p/19q codeletion by using real‐time PCR intraoperatively. We report the usefulness of this method in this presentation.

Objective: 58 specimens obtained during surgery from March to November 2017, IDH 1/2 gene mutations and 1p/19q codeletion were evaluated intraoperatively by real‐time PCR. IDH 1/2 gene mutations were detected using HRM, and SNP genotyping was used for TERT promoter mutations expected as a surrogate marker for 1p/19q codeletion.

Result: Each gene mutation was detected in approximately 90 minutes from DNA extraction of obtained surgical tissue to analysis. The accuracy of HRM of IDH 1/2 mutations was 100% (57/57 cases) evaluated by the result of IDH1‐R132H IHC or Sanger sequencing, and SNP genotyping of TERT promoter mutations was 97.2% (35/36 cases). There was almost no difference from final genetic information.

Conclusion: Real‐time PCR is feasible as an intraoperative molecular diagnosis. The accuracy of diagnosis is very high and it can be evaluated in a short time, so it's useful for decision making during operation.

Clinicopathologic study of epithelioid glioblastoma and gliosarcoma

Shunsuke Tsuzuki¹; Yoshihiro Muragaki^1,2; Takashi Maruyama^1,2; Masayuki Nitta^1,2; Taiichi Saito^1,2; Takashi Komori³; Takakazu Kawamata¹

¹Department of Neurosurgery, Tokyo Women's Medical University; ²Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University; ³Tokyo Metropolitan Neurological Hospital

Epithelioid glioblastoma (GBM) is rare variant of GBM and established in classification of WHO 2016. This tumor have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM even if tumor removal and intensive chemoradiotherapy were performed. Gliosarcoma also an uncommon histopathological feature and consists of both gliomatous and sarcomatous components, and the gliomatous component exhibits the feature similar to those of GBM. The histogenesis of gliosarcoma has been controvertial for a long time, but recently it has been established that the sarcomatous component is derived from the heterodifferentiation of GBM cells. Cytogenetic studies have demonstrated that gliosarcoma is a variant of primary (de novo) GBM. These tumors were rare, but the prognosis was poor. Thus, accurate diagnosis and effective therapy for epithelioid GBM and gliosarcoma are required.10 consecutive patients (Epithelioid GBM 5, Gliosarcoma 5) aged 33‐76 years were diagnosed with epithelioid GBM/gliosarcoma by pathological and immunohistochmical analysis at TWMU from 2012 to 2018. We reviewed these cases recurrence and prognosis, mutation such as BRAF V600E, INI 1. A new therapeutic approach is necessary for the treatment for these tumors.

Analysis of site‐specific expression of cancer stem cell markers in glioblastoma

Masahiro Nishikawa¹; Akihiro Inoue¹; Shohei Kohno²; Shiro Ohue³; Riko Kitazawa⁴; Hajime Yano⁵; Yonehiro Kanemura^6,7; Junya Tanaka⁵; Takanori Ohnishi⁸; Takeharu Kunieda¹

¹The Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Japan; ²The Department of Neurosurgery, Himeji Red Cross Hospital, Himeji, Japan; ³The Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Japan; ⁴The Department of Molecular Pathology, Ehime University Graduate School of Medicine, Toon, Japan; ⁵The Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Toon, Japan; ⁶The Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁷The Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan; ⁸The Department of Neurosurgery, Washoukai Sadamoto Hospital, Matsuyama, Japan

A subpopulation of glioma stem‐like cells(GSCs) is thought to be a main cause for the invariable recurrence following maximum resection and radio‐chemotherapy in glioblastoma multiforme (GBM). As most GSCs that are located in the perivascular and perinecrotic niches should be removed during tumor resection, it is very important to know where surviving GSCs are localized. Here, we investigated the existence and functions of GSCs in the tumor periphery, which is considered to constitute the invasion niche for GSCs in GBM, by analyzing expression of stem cell markers and stem cell‐related molecules and measuring particular activities of cultured GSCs. In addition, the relationship between GSCs expressing particular stem cell marker and pathological features on MRI and prognosis in GBM patients was analyzed. We showed that GSCs that expressed high levels of CD44 were present in the tumor periphery. Cultured GSCs obtained from the tumor periphery were highly invasive and migratory activities, both of which were markedly inhibited by CD44 knockdown. Higher expression of CD44 in the tumor periphery than in the core tended to correlate with a highly invasive feature on MRI and was associated with early tumor progression and worse survival, whereas lower expression of CD44 in the tumor periphery corresponded to low invasion and was associated with longer survival. These results may imply the significance of GSCs with high levels of CD44 expression in the tumor periphery compared to the core, not only in tumor invasion but also rapid tumor progression and short survival in patients with GBM.

RAMBO inhibits bevacizumab‐induced glioma invasion

Yusuke Tomita¹; Kazuhiko Kurozumi¹; Yuji Matsumoto¹; Yasuhiko Hattori¹; Toshihiko Shimizu¹; Yoshihiro Otani^1,2; Kentaro Fuji¹; Tomotsugu Ichikawa¹; Balveen Kaur²; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ²Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA

Introduction: The molecular‐targeting therapeutic agent taking vascular endothelial growth factor (VEGF) as a target has demonstrated convincing therapeutic benefit in glioblastoma patients. However, anti‐VEGF therapy has also been reported to induce glioma invasion. In this study, we evaluated the effects of a oncolytic herpes simplex virus on the glioma invasion induced by anti‐VEGF thrapy.

Methods: Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO) is composed of the cDNA encoding for human vasculostatin (Vstat120), driven by the HSV‐1 IE4/5 promoter, within the backbone of an attenuated HSV‐1 virus (HSVQ). We used bevacizumab as a anti‐VEGF therapeutic agent. The effect of the combination of RAMBO with bevacizumab in vitro was assessed by cytotoxicity, migration, and invasion assays. For in vivo experiments, U87deltaEGFR cells were stereotactically injected into the brain of nude mice. Seven days after tumor implantation, RAMBO was injected into the tumor and then bevacizumab was administered intraperitoneally twice per week.

Results: RAMBO significantly reduced both the migration and invasion of glioma cells induced by bevacizumab. In mice treated with a combination of bevacizumab and RAMBO, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab as monotherapy.

Conclusion: RAMBO suppressed bevacizumab‐induced glioma invasion in vitro and in vivo. RAMBO and bevacizumab combination increased anti‐tumor effect. These results may lead to a promising treatment strategy of malignant glioma.

Tumor‐associated macrophages in glioblastoma

Takashi Sasayama¹; Kazuhiro Tanaka¹; Yuichiro Koma²; Masahiro Maeyama¹; Yuich Fujita¹; Satoshi Nakamizo³; Masamitsu Nishihara⁴; Takanori Hirose⁵; Hiroshi Yokozaki²; Eiji Kohmura¹

¹Department of Neurosurgery, Kobe University; ²Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; ³Department of Neurosurgery, Hyogo Brain and Heart Center, Himeji, Japan; ⁴Department of Neurosurgery, Nishi Kobe Medical Center, Kobe, Japan; ⁵Department of Pathology for Regional Communication, Kobe University Hospital, Kobe, Japan

Introductuion: A role of macrophage in glioblastoma is not clear yet.

Methods: Tumor‐associated macrophage (TAM)‐like macrophages were prepared from peripheral blood mononuclear cell (PBMC). U87 cells were co‐cultured with TAM‐like macrophages, and invasion/migration assay was performed. U87 cells were inoculated with TAM‐like macrophages into mouse brains and histological examinations were performed. We evaluated the specimens resected from thirty‐three patients with glioblastoma (GBM). We investigated the infiltration of TAMs. Also, we examined the association between infiltration levels of TAM and cerebrospinal fluid (CSF) cytokines and patients’ survival.

Results: Invasion/ migration abilities were increased in U87 cells co‐cultured with TAM‐like macraphages. JAK‐STAT3 pathway was mores activated in inoculated U87 tumors with TAM‐like macrophages, compared with control. The mean infiltration rate of CD163‐positive macrophages in all GBM specimens was 23.9% (3.7 ˜ 64.7%). The rate of TAM was significantly correlated with CSF IL‐6 level ((ex.) p < 0.001). In relationship between TAMs and progression free survival (PFS), glioblastomas with higher levels of TAMs had tendency of shorter OS in comparison with those with lower levels of TAMs (p = 0.046). In addition, CD163 positive TAMs expressed abundant IL‐6 and CSF IL‐6 was prognostic factor in GBMs.

Conclusions: We observed high infiltration of CD163‐positive TAMs in GBM specimens. The infiltration levels of TAMs correlated with IL‐6 levels in CSF. The infiltration level of TAMs may be associated with the prognosis of patients with GBMs.

Hypoxia‐mediated cancer stem cells in pseudopalisades with activation of hypoxia‐inducible factor‐1α/Akt axis in glioblastoma

Madoka Inukai¹; Atsuko Hara¹; Yoshie Yasui²; Ichiyou Shibahara²; Toshihiro Kumabe²; Makoto Saegusa¹

¹Department of Pathology, Kitasato University School of Medicine, University of Kanagawa, Japan; ²Department of Neurosurgery, Kitasato University School of Medicine, University of Kanagawa, Japan

Introduction: Pseudopalisades (Ps) around necrotic foci are severely hypoxic and overexpress hypoxia‐inducible factor (HIF) in glioblastoma (GBM). Hypoxic regions have been proposed as one of several distinct niches for cancer stem cells (CSCs) in GBM, but little is known about the association between Ps features and CSC properties. Herein, we focused on the biological role of Ps lesions. In clinical cases of GBM, expression of hypoxia‐related molecules including HIF‐1α, Glut‐1, p27^Kip1 as well as pAkt, was significantly increased in perinecrotic Ps lesions compared with non‐necrotic areas and perinecrotic lesions lacking Ps features. Significantly higher expression levels of several CSC‐related markers, including CD133, Sox2, CD44s, and aldehyde dehydrogenase (ALDH) 1, were also observed in Ps lesions, which were positively correlated with expression of hypoxia‐related molecules and pAkt. Ps lesions also showed increased number of apoptotic cells and decreased bcl‐2 and survivin expression compared with the surrounding tissue. Short‐term exposure of astrocytoma cell lines to cobalt chloride (CoCl2), which is known to mimic the effect of hypoxia, caused an increase in expression of both hypoxia‐ and CSC‐related markers, in line with increases in the ALDHhigh cell population and number of spheroids. Inhibition of endogenous Akt by LY294002 resulted in decreased expression of Sox2, ALDH1, and CD133, leading to enhancement of CoCl2‐mediated apoptotic events due to altered ratio of bcl‐2 to bax expression. These findings suggest that Ps lesions within GBM may serve as a specialized hypoxic niche, in which the HIF‐1α/pAkt axis is activated, in response to severe hypoxia.

Role of CCN1 induction by YAP/TAZ in malignant glioma

Atsuhito Uneda¹; Kazuhiko Kurozumi¹; Atsushi Fujimura²; Kentaro Fujii¹; Toshihiko Shimizu¹; Yusuke Tomita¹; Yasuhiko Hattori¹; Yuji Matsumoto¹; Nobunari Tsuboi¹; Isao Date¹

¹Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ²Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Extracellular matrix (ECM) interacts with cancer cells and regulates their growth and survival. CCN family member 1 (CCN1, also known as CYR61) is a matricellular protein that regulates various signal transductions by interaction with ECM and cell surface molecules. Our previous study showed that high CCN1 expression correlated with poorer prognosis in patients with glioblastoma. Here, we focused on the effects of CCN1 induction by the mechanical signal‐sensitive transcriptional co‐activators, Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ, also known as WWTR1), in malignant glioma. First, we analyzed available glioma datasets to determine correlations between expression of CCN1, WWTR1 and YAP1 and survival of patients with glioma. Next, we analyzed differential gene expression of several glioma data sets. Finally, we performed knock‐down and overexpression analysis of these genes, using human malignant glioma cell lines. Expression of CCN1, WWTR1 and YAP1 correlated with prognosis in glioma patients and mesenchymal profiles. We found genes associated with adhesion, ECM and epithelial‐mesenchymal transition to correlate with expression of CCN1, WWTR1 and YAP1. YAP/TAZ induced CCN1 expression via the TEA domain family member transcriptional factor, which affected colony‐forming capacity, sphere‐forming capacity, and cytoskeletal remodeling. We conclude that YAP/TAZ may promote malignant glioma progression by induction of CCN1. These results indicate that YAP/TAZ could be new targets for treating malignant glioma.

Predictive markers for MGMT promoter methylation in glioblastomas

Tokunori Kanazawa¹; Hirokazu Fujiwara², Masahiro Jinzaki², Masahiro Toda¹, Kazunari Yoshida¹; Hikaru Sasaki¹

¹Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan; ²Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan

The Promoter methylation status of the O6‐methylguanine‐DNA methyltransferase (MGMT) gene has been described as the most important predictor for chemotherapeutic response and patients’ survival in glioblastomas (GBs). Therefore, prediction of the MGMT promoter methylation status by imaging would help to preoperatively decide the overall treatment strategy as well as surgical strategy including placement of BCNU wafers. This study aimed to detect imaging parameters to predict MGMT promoter methylation in GBs using a commercially available software. We investigated 3 imaging features (ring enhancement, location and laterality) and apparent diffusion coefficient (ADC) parameters in 48 newly diagnosed glioblastomas treated at Keio University Hospital in 2006 or later. For ADC, texture analyses were performed. Regions of interest (ROIs) were drawn manually with reference to the relatively higher signal on contrast‐enhanced T1‐weighted images excluding necrotic and cystic regions. Mean ADC value and ADC histogram parameters including kurtosis, skewness and entropy were compared with MGMT promoter methylation. Each parameter was evaluated if any correlation with MGMT promoter methylation, and the statistically significant parameters were correlated with MGMT positive cell ratio in immunohistochemistry. ADC entropy and mean ADC value were significantly associated with MGMT promoter methylation. The combination of ADC entropy and mean ADC value predicted MGMT promoter methylation with PPV of 81.2%, specificity of 88.9%. ADC entropy and mean ADC value were negatively correlated with MGMT positive cell ratio in immunohistochemistry. This study demonstrated that texture analyses of ADChistograms in GBs using a commercially available software were useful for predicting MGMT promoter methylation.

Prognostic impact of TERT promoter mutation suggests its utility as a surrogate marker for 1p/19q codeletion in IDH mutated gliomas

Hideyuki Arita^1,2; Makoto Ohio³; Taishi Nakamura⁴; Kaoru Tamura⁵; Yohei Miyake⁶; Kuniaki Saito⁷; Shota Tanaka⁸; Fumi Higuchi⁹; Yonehiro Kanemura¹⁰; Koichi Ichimura¹

¹Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan; ²Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan; ³Department of Neurosurgery and Neuro‐Oncology, National Cancer Center Hospital, Tokyo, Japan; ⁴Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; ⁵Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan; ⁶Department of Neuro‐Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan; ⁷Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan; ⁸Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ⁹Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan; ¹⁰Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan

Molecular testing for 1p/19q codeletion is mandatory for the diagnosis of oligodendrogliomas in the diagnostic system of the CNS WHO 2016. Although the great majority of IDH mutated‐1p/19q codeleted tumors harbor TERT promoter mutations, TERT is not incorporated in the current diagnostic system. In this study, we compared the prognostic impact of TERT promoter mutation with that of 1p/19q codeletion in IDH mutated gliomas in order to evaluate the utility of TERT as a surrogate marker for 1p/19q codeletion. We analyzed a series of 286 glioma cases with IDH1/2 mutation (141 grade II, 129 grade III, and 16 grade IV case). TERT mutations and 1p/19q codeletion were observed in 155 and 148 cases, respectively. Those alterations were overlapped in 144 cases. A Cox proportional hazard model showed favor prognostic impact of both TERT mutation (HR 0.32, p &lt: 0.0001) and 1p/19q codeltion (HR 0.36, p &lt: 0.0001) on survival. When incorporating clinical background including patient age, WHO grade, and adjuvant therapy in the multivariate analysis, TERT mutation had positive impact on survival, but the impact of 1p/19q codeletion was not significant. Thus, TERT mutated tumor overlapped the 1p/19q codeleted tumors and was a favor prognostic factor in IDH mutated tumors as well as 1p/19q codeletion. Our results indicate that TERT may be a surrogate marker for 1p/19q codeletion and warrants further validation study.

Pathological investigation of novel spray‐type fluorescent probes for brain tumors

Shota Tanaka¹; Yosuke Kitagawa¹; Akira Ogasawara²; Yugo Kuriki²; Kyoko Yamamoto³; Mako Kamiya^2,3; Yasuteru Urano^2,3; Nobuhito Saito¹

¹Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ²Laboratory of Chemistry and Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo; ³Laboratory of Chemical Biology and Molecular Imaging, Graduate School of Medicine, The University of Tokyo

Objective: A fluorescent probe such as 5‐aminolevulinic acid achieves greater extent of resection in glioma surgery and thus serves as a valuable surgical adjunct. However, its sensitivity and specificity are yet to be perfectly satisfactory. Our novel spray‐type fluorescence system using green hydroxymethyl rhodamine green (HMRG) probes has been tested for brain tumors. In this study, we investigated on red dimethyl silicone rhodamine 600 (2MeSiR600) probes, which have a higher sensitivity for peptidase activity than HMRG probes.

Materials and Methods: Fresh tumor tissues as well as fresh frozen tissues harvested from gliomas resected at our institutions were used in this study. The probe library included over 400 types with different combinations of amino acids attached to 2MeSiR600. Fluorescence intensity was measured over time after probes were applied to homogenized lysates made from fresh frozen tissues. Fluorescent probes which clearly discerned the tumor area from the peripheral area were selected, and then applied to fresh tumor tissues to confirm their selectivity. Tumor tissues were fixed with formalin and stained with hematoxylin and eosin. Immunohistochemistry staining was also performed. The correlation between fluorescence intensity and histopathology including cell density and MIB‐1 labeling index was investigated.

Results: Probe screening demonstrated some 2MeSiR600 probes exhibited significantly higher fluorescence intensity in the peripheral area compared to the tumor area, which was confirmed when they were applied to fresh tumor tissues.

Conclusion: 2MeSiR600 probes which selectively fluoresce the peripheral area may enable highly selective tumor recognition in conjunction with 5‐aminolevulinic acid or our HMRG probes.

Radiomics analysis for detection of IDH mutation of glioma using diffusion weighted sequence images

Satoshi Takahashi¹; Wataru Takahashi²; Shota Tanaka¹; Akihiro Haga³; Takahiro Nakamoto²; Yuuichi Suzuki²; Akitake Mukasa¹; Shunsaku Takayanagi¹

¹Department of Neurosurgery, The University of Tokyo, Tokyo, Japan; ²Department of Radiology, The University of Tokyo, Tokyo, Japan; ³Department of Medical Image Information Science, The University of Tokushima, Tokushima, Japan

Objective: Creating a machine learning model using diffusion‐weighted sequence images is effective for malignancy diagnosing of glioma. However, it is unknown whether IDH‐1 and 2 mutations, which are the most important mutations in glioma, can be predicted using diffusion‐weighted sequence images. The purpose of our research is to predict IDH mutation by machine learning model made by diffusion‐weighted sequence images.

Methods: Between August 2014 and July 2017, 38 consecutive patients with suspected glioma and preoperative MRI including diffusion coefficient (ADC), fractional anisotropy (FA), mean kurtosis (MK), were included in the study. All IDH mutations were identified by Sanger Sequencing. A volume of interest (Voi) was created manually and applied to T2‐weighted images, diffusion‐weighted images (DWI), ADC, FA, MK. 476 per imaging sequence and 2856 features were extracted.

Results: 39 datasets were obtained. The number of cases for IDH‐1,2 mutation and wild‐type was 21 cases of IDH‐1 mutation (3 Diffuse Astrocytoma, 8 Anaplastic Astrocytoma, 4 Oligodendroglioma, 3 Anaplastic Oligodendroglioma, 3 Glioblastoma), 18 cases of wild‐type(2 Anaplastic Astrocytoma, 16 Glioblastoma). An IDH‐2 mutation was not observed in our cases. Features were narrowed down using Recursive Feature Elimination (RFE). The most accurate machine learning model was created using the extracted eight features from ADC, Fa, and MK. The best AUC was 0.95 plusminus 0.02 in SVM(kernel is rbf, c is 1.0).

Discussion: Imaging sequences useful for IDH‐1 mutation identification are ADC, MK, FA, similar to malignancy diagnosing of glioma. But useful features were different. Machine learning models may be useful for identifying IDH‐1 mutations.

Pathological consideration of spray type new fluorescent probe for glioblastoma

Yosuke Kitagawa¹; Shota Tanaka¹; Akira Ogasawara²; Yugo Kuriki²; Kyoko Yamamoto³; Mako Kamiya³; Yasuteru Urano^2,3; Nobuhito Saito¹

¹Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo; ²Laboratory of Chemistry and Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo; ³Laboratory of Chemical Biology and Molecular Imaging, Graduate School of Medicine, The University of Tokyo

Objectives

5‐ALA is commonly used intraoperative diagnostic tool in malignant glioma surgery, which has been proved to be effective for radical tumor resection and prognosis improvement. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re‐administration. We aim to develop a new safe fluorescent labeling system, which can be repeatedly administered by spray during surgery, using fluorescence probes for peptidases based on hydroxymethyl rhodamine green (HMRG) originally designed at our university for cancer detection, complementing 5‐ALA. Here, we report the correlation between histopathological findings and the fluorescence intensity of probes selected from our experiment.

Methods

More than 320 types of HMRG fluorescent probes were applied to homogenized lysates. The fluorescence intensity after application was measured over time, and selected probes were used for the fresh specimens. Correlation between fluorescence intensity and histological findings, such as cell density or Ki‐67 labeling index was validated.

Results

Top seven probes with higher fluorescent reactions and more precision in the identification of glioblastoma were selected from the experiments using homogenized lysates and fresh specimens. Samples showing no fluorescence after applying one of the selected probes tend to contain microvascular proliferation and necrosis within the same pathology.

Discussions

As our HMRG probes are designed to target protease, tissues without fluorescence have less or different enzymic activity compared to those with high fluorescence.

The treatment course and radiological findings in malignant glioma cases treated by Bevacizumab over the long term

Atsushi Kambe¹; Yuichiro Nagao¹; Sadao Nakajima¹; Koichi TORIHASHI¹; Hiroki Yoshioka¹; Tetsuji Uno¹; Makoto Sakamoto¹; Satoshi Kuwamoto²; Yasushi Horie²; Masamichi Kurosaki¹

¹Division of Neurosurgery, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Tottori, Japan; ²The Department of Pathology, Tottori University Hospital

Background and Aim: Bevacizumab(BEV) was approved as malignant glioma treatment from June 2013, and a lot of malignant glioma cases treated by BEV are accumulated in various institutions in Japan. We examined the features of treatment course and radiological findings in the cases treated by BEV over the long term.

Objective and Method: Total 42 cases were treated by BEV from June 2013 to March 2018 in our institute. 6 cases treated over two years were assessed.

Results: There were 4 men and 2 women with a median age of 53.8 years(range 39‐76 years). The pathological diagnosis was 1 glioblastoma, 4 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. Bevacizumab treatment was performed median 48 courses(range 36‐62 courses) and treatment period was median 30.8 months(range 24‐46 months). Focal recurrence was appeared in 5 of 6 cases during treatment period and the treatment was discontinued in 3 cases because of the relapse(2 cases) and proteinuria(1 case). Head CT scan revealed the appearance of calcification inside tumor lesions in 5 of 6 cases after Bevacizumab treatment. In pathological findings, the lesions were mixed with the features of ischemia and calcification surrounding with scattered tumor cells.

Conclusions: We examined the treatment course and radiological findings in 6 cases treated by BEV over 2 years. Calcification was appeared in the tumor lesions after BEV treatment in 5 of 6 cases, suggesting the possibility of therapeutic effects by BEV in pathological findings.

Evaluating clinical factors for predicting response to bevacizumab in patients with malignant glioma

Shinji Yamashita; Kiyotaka Yokogami; Fumitaka Matsumoto; Kiyotaka Saito; Asako Mizuguchi; Takashi Watanabe; Hajime Ohta; Hideo Takeshima

Neurosurgery department, University of Miyazaki, Miyazaki, Japan

Background: In June 2013 Bevacizumab (Bev) was approved as a treatment for malignant glioma. Since that time, the drug has mainly been used to treat recurrent disease. Although some patients were able to maintain their QOL for a certain period due to effects of Bev, other patients became progressively worse. In this study, we attempted to explore the clinical and genetic factors for predicting response to Bev in patients with malignant glioma.

Patients and Methods: From September 2013 to July 2017, 31 patients with recurrent malignant glioma were treated with Bev at our hospital. Ten patients were Grade 3 and 21 patients were Grade 4. The male‐female ratio was 17:14, and the median age was 61 (range, 23‐80). Bev response was defined as patients whose tumors decreased on magnetic resonance imaging (MRI) examination, or who maintained stable QOL for more than three months. Candidate clinical and genetic factors for predicting Bev response were evaluated by comparing responders to non‐responders.

Results: In all, 16 patients were responders and 15 were non‐responders. Disease dissemination and the presence of multiple lesions were the strongest factor for predicting non‐responders (p = 0.0049). Histology (p = 0.013), time of introduction (p = 0.025) and Karnofsky Performance Scale (KPS, p = 0.072) also predicted response. Moreover, analysis of gene expressions associated with vascularization showed that NOTCH1 was correlated with favorable response to Bev (p = 0.0008).

Conclusions: Recurrence pattern, histology, time of introduction, and KPS reduced response to Bev. Additionally, gene expression of NOTCH1 may act as a potential biomarker for treatment with Bev.

Combined modality therapy strategy based on histologic diagnosis of PPTID

Yasuo Aihara¹; Kentaro Chiba¹; Takashi Komori²; Takakazu Kawamata¹

¹Department of Neurosurgery Tokyo Women's Medical University, Tokyo, Japan; ²Tokyo medicine research institute brain tumor pathological laboratory

Objectives: PPTID (Pineal parenchymal tumor of intermediate differentiation) is a middle property extremely rare tumor with middle character of pineocytoma and pineoblastoma. For this tumor, standard treatment is not established histologically for gradeII‐III. (Case) 40 years old woman. It occurred for dizziness at transient diplopia, from 14 years ago and the Pt had pointed out the pineal tumor and hydrocephalus. For the next year, a neuroendoscopical third ventriclurostomy and tumor biopsy was done. (Dx:pineocytoma), and the GKS (20 Gy) was selected for postoperative residual tumor mass. The tumor size had reduced at one time, but midbrain hidden part ‐ aqueduct of midbrain showed the recurrence of the mass lesion in the course of ten years. We performed complete removal as possible subsequently in our hospital because of progressive increasing of tumor.(Histopathology findings)the circular nucleated atypical cells which N/C ratio is high, and are relatively uniform multiply thickly. The tumor cells were synaptosphysin diffusely‐positive, and mitotic images increased (mitotic index 6/10 HPFs) and there were few hot nodules of neurofilament and was findings of the gradeIII equivalency. (MIB‐1 = 5.8%) (Clinical course)Based on GKS (20 Gy), the additional local site radiation was decided to be difficult. So observation follow‐up was selected without chemo‐radiotherapy.

Conclusion: The definition of the pathologic finding to distinguish gradeII‐III of PPTID is vague, and the clinical course is various. So, the decision making for the time of the intervention of the surgical treatment and the selection of the chemo‐radiotherapy (local radiation therapy, whole brain total spinal radiation) should be careful.

Experience of intraoperative Ki‐67 staining using Histotech R‐IHC at our hospital

Hiroyuki Masuda; Shuhei Kubota; Chie Matsuura; Yutaka Fuchinoue; Shinichi Okonogi; Yasuhiro Node; Shunpei Ando; Kosuke Kondo; Naoyuki Harada; Nobuo Sugo

Department of Neurosurgery (Omori), School of Medicine, Faculty of Medicine, Toho University

Intraoperative rapid pathological diagnosis in brain tumors is an essential test for determining tumor types and extirpation ranges. Diagnosis requires precision and speed, and special immunostaining requiring more than one day to fix paraffin has never been used for rapid diagnosis until now. However, the emergence of the rapid immune system Histotech‐R‐IHC(Rapito) enabled immune staining in a short period of time. Rapito is a device that can perform special immunostaining in about 30 minutes by causing an antigen‐antibody reaction by electric field non‐contact stirring method. In addition, this machine can use both crushed specimen and frozen specimen, and it is characterized by not requiring paraffin fixation in immunostaining. Besides, it is said that almost the same result as dyeing by permanent specimen can be obtained. Therefore, we focused on the rapidity of this machine and dyed Ki ‐ 67 used as cell proliferation marker intraoperatively. In gliomas where the excision rate and prognosis, the correlation between malignancy and Ki ‐ 67 are known, the rapid pathological diagnosis plays a major role in determining the extent of excision and the presence or absence of the use of Giardia deal. However, when frozen sections are used during rapid diagnosis, psychological evaluation may be difficult due to artifacts. Therefore, it is thought that staining Ki ‐ 67 intraoperatively has important significance. We report the dyeing experience of Ki ‐ 67 in our department, which introduced Rapito with the literature consideration.

Clinicopathological analysis of tyrosine kinase receptors in meningiomas‐Meningiomas with high expression of VEGFR‐2 had shorter recurrence/regrowth‐free survival

Satoko Nakada¹; Yasuo Sasagawa^2,3; Osamu Tachibana²; Hideaki IIduka²; Nozomu Kurose¹; Sohsuke Yamada¹; Takayuki Nojima^1,4

¹Department of Laboratory Medicine and Pathology, Kanazawa Medical University, Uchinada, Japan; ²Department of Neurosurgery, Kanazawa Medical University, Uchinada, Japan; ³Department of Neurosurgery, Medical school, Kanazawa University, Kanazawa, Japan; ⁴Department of Pathology, Kanazawa University Hospital, Kanazawa, Japan

WHO grade 2/3 meningiomas recur frequently and molecular target therapy against these meningiomas has not established yet. In this study, we analyze correlation between expressions of tyrosine receptors in meningiomas and recurrence/regrowth in meningiomas.

Materials and Methods: All 74 patients were received surgery in our hospital from 2001 to 2014. Clinical data including age, sex, tumor location, Simpson grade was collected. All histology of meningiomas were reviewed on WHO 2016. Immunohistochemistry for tyrosine receptors (VEGFR‐1/2/3, PDGFR‐alpha/β and c‐kit) was performed by using tissue microarray of meningiomas. All data was analyzed statistically.

Results: Median age was 64 years old. Median follow‐up after diagnosis was 60.4 months. Female were 52 (70%). Forty two (56%) tumors were located in skull base. Simpson grade 1 to 3 resection was performed in 52 tumors (64%). WHO grade 2/3 meningiomas were 17. VEGFR‐1 were positive in 31 tumors, VEGFR‐2 in 41, VEGFR‐3 in 55, PDGFR‐alpha in 63, PDGFR‐beta in 60, c‐kit in 52. VEGFR‐2 was positive in 14 (82 %) WHO grade 2/3 meningiomas. In univariate analysis, meningiomas with expression of VEGFR‐2 had higher recurrence rate with statistical significance (p = 0.035) and also Simpson grade, tumor size, WHO grade, Ki‐67 and PgR had. In multivariate analysis, only WHO grade and skull base location were correlated with recurrence.

Conclusion: VEGFR‐2 might play an important role in malignant of recurrent/ regrowth meningiomas and inhibitors against VEGFR‐2 might be a candidate for the molecular therapy to recurrent meningiomas.

Mammosommatotroph pituitary adenoma coexisting with symptomatic suprasellar arachnoid cyst‐ diagnosis and treatment for co‐existence of suprasellar cyst and pituitary adenoma –

Osamu Tachibana¹; Shou Takada¹; Atsushi Nakagawa²; Daisuke Koya²; Mariko Doai³; Munetaka Matoba³; Satoko Nakada⁴; Nozomu Kurose⁴; Sousuke Yamada⁴; Hideaki Iiduka¹

¹Department of Neurosurgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan; ²Department of Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan; ³Department of Radiology, Kanazawa Medical University, Uchinada, Ishikawa, Japan; ⁴Department of Clinical Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan

Suprasellar or sellar cystic lesions lead to a difficulty in preoperative diagnosis. Co‐existence of symptomatic suprasellar arachnoid cyst and pituitary adenoma has been very rarely reported. Here, a functioning pituitary adenoma and a suprasellar arachnoid cyst in the same patient is presented, and possible etiopathogenetic mechanisms and surgical treatment are discussed. A 52‐year‐old woman was admitted to the hospital with a visual disturbance. Preoperative MR revealed a mass lesion in the sella turcica and a coexisting suprasellar cyst. Endocrinological examination revealed high concentration of serum growth hormone (18.1 ng/ml), insulin‐like growth factor (722 ng/ml +8SD) and prolactin (35ng/ml). Intra‐operative findings showed pituitary adenoma in the sella turcica and yellowish clear cyst fluid. Extracapsular dissection was performed in this adenoma and a fenestration was made between the suprasellar cyst cavity and suprasellar subarachnoid space. Histopathology showed GH and PRL positive pituitary adenoma and revealed pseudocapsule and true capsule between adenoma with cyst. Suprasellar cyst capsule was composed of arachnoid membrane and immunoreactive for anti‐vimentin, and EMA antibodies. After surgery, this patient with acromegaly was complete remission and her visual disturbance was recovered. The possible mechanism to explain the coexistence would be discussed and the diagnosis and treatment for co‐existence of suprasellar cyst and pituitary adenoma.

Pay attention to germinomatous component of negative for c‐kit expression on IHC

Kentaro Chiba¹; Yasuo Aihara¹; Takashi Komori²; Takakazu Kawamata¹

¹The department of neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; ²Tokyo Metropolitan Neurological Hospital

Introduction: Germinoma is well‐responded to chemo‐ and radiotherapy and could be curable these days. On the other hand, 10% of germinoma and non germinomatous germ cell tumors (NGGCTs) are resistant to adjuvant therapy.

Cases: 41 intracranial germ cell tumor cases who underwent biopsy or surgical resection during the period of 2004 to 2018 at Tokyo Women's Medical University (Age: 6‐39 years old): 26 cases of germinoma and 15 cases of NGGCTs.

Result: Outcome: 39 cases of CR and two cases died from primary disease: one case is 17 years old boy, pineal region mixed germ cell tumor (germinoma + choriocarcinoma), another case is 13 years old boy, basal ganglia germinoma.

Pathology: PLAP, c‐kit expression on IHC: PLAP (85.7%), c‐kit (88.4%) were positive. Majority of germinoma component were membranous positive for c‐kit, whereas all teratoma component were membranous negative for c‐kit. There were 3 cases whose germinomatous component were negative for c‐kit expression, of these three, two cases experienced dissemination and died for primary disease.

Discussion/Conclusion: GCTs with c‐kit negative germinomatous component need to be paid attention. The existence of KIT gene mutation is said to be less correlated with c‐kit expression. Correlation between c‐kit expression on IHC and prognosis and its biological meaning should be discussed in the future.

Establishment of two cell lines from a case with SHH type TP53 mutated medulloblastoma

Kiyotaka Yokogami; Asako Mizuguchi; Shinji Yamashita; Kiyotaka Saito; Fumitaka Matsumoto; Takashi Watanabe; Hideo Takeshima

Department of Neurosurgery, Section of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki

As described in the MAGIC project, new treatment protocols will be established according to the four subtyps of medulloblastoma. Basic experiments of medulloblastoma should be performed using cells corresponding to 4 subtype classifications, but there is only one type of commercially available cell line of SHH type TP53 mutated. We report that two different cell lines were established from a case with SHH type TP53 mutated medulloblastoma. The surgical sample was subjected to primary culture with two types of culture medium (serum free culture medium for cancer stem cells (CSC media) or D‐MEM supplemented with 10% FBS), and each subculture over 1 year (507 CSC, 507 FBS). 507 CSC proliferated in a floating state which formed an irregular spheroid. Laminin coating dish adhered to dish under CSC media and proliferated, but it did not adhere to dish even when cultured with 10% FBS‐added D‐MEM. On the other hand, 507 FBS proliferated in a state attached to dish, but the growth rate was about half of 507 CSC. Examination of gene expression in each cells revealed that Gli 2 with high expression in SHH type was comparable, but N‐myc, Msi1, Msi2, Sox2 and Prom 1 were very high in 507 CSC, Notch 1, 3, Jag1, PDGFRa, ITGa6, b1 were high in 507 FBS.

Atypical Teratoid / Rhabdoid Tumor having been elucidated in 20 years

Hidehiro Oka^1,2,4; Mari Kusumi¹; Mitsuru Dan¹; Koji Kondo¹; Toshihiro Kumabe¹; Arie Perry³; Bernd Scheithauer⁴

¹Department of Neurosurgery, Kitasato University Medical Center; ²Department of Neurosurgery, Kitasato University, Sagamihara, JAPAN; ³Department of Pathology, UCSF, San Fransisco, U.S.A; ⁴Department of Pathology, Mayo Clinic and Mayo Foundation, Rochester, U.S.A

Introduction: Atypical Teratoid / Rhabdoid Tumor (AT/RT) is the embryonal malignant central nervous system tumor which Rorke and others proposed for the first time in 1996. Authors reported the first example in this country in 1998 and reviewed it mainly on a case of Mayo Clinic in 1999. This AT/RT might have been misdiagnosed as medulloblastoma and PNET. I investigated it including an own omen example where it was elucidated this time to in 20 years after this tumor proposal.

Surgical strategy for solitary skull lesion of Langerhans cell histiocytosis from pathological findings

Akira Gomi¹; Hirofumi Oguma²; Akira Morimoto³

¹Department of Pediatric Neurosurgery, Jichi Children's Medical Center Tochigi, Jichi Medical University, Tochigi, Japan; ²Department of Neurosurgery, Jichi Medical University, Tochigi, Japan; ³Department of Pediatrics, Jichi Children's Medical Center Tochigi, Jichi Medical University, Tochigi, Japan

Introduction: We considered the treatment policy of single‐system single‐site type (SS‐s type) of Langerhans Cell Histiocytosis (LCH) by reviewing the pathological findings.

Methods: The clinical course was examined retrospectively for 9 cases of skull SS‐s type LCH who underwent surgery at our institution from 2008 to 2017.

Results: At the boundary with the surrounding bone, multinucleated giant cells (osteoclasts) were infiltrated into the bone. The periosteum showed tumor cell infiltration in the surroundings. The galea showed a collection of inflammatory cells but no tumor cell infiltration. There is a very small amount of tumor cells in the outer layer of dura, but mainly inflammatory cell infiltration. From these results, in order to completely remove the lesion, it is necessary to remove the surrounding bone and the periosteum of the lesion part, and it is also necessary to remove the outer layer of the dura mater, but the resection of the galea was considered unnecessary.

Discussion: The extent of surgical removal necessary for total removal is wide.

Relevance of new classification and clinical course in so‐called primitiveneuroectodermal tumor

Mario Suzuki¹; Akihide Kondo¹; Atsushi Arakawa²; Hajime Arai¹

¹Department of Neurosurgery, Juntendo University School of Medicine, Tokyo, Japan; ²Department of pathology, Juntendo University School of Medicine, Tokyo, Japan

Background: The entity of primitive neuroectodermal tumor (PNET) was abandoned from the revisedWHO classification tumors of the central nervous system (CNS) in 2016. PNET had beendefined as highly proliferative small round blue cells that showed neuronal, glial, andepithelial or mesenchymal features. Integrated diagnosis re‐classified this tumor inaccordance with morphology and molecular background. In this study, we reviewed our tumor samples, those were diagnosed as PNET previously, histopathologically and genetically, and considered whether the new classification hadrelevance for clinical outcome.

Material and Methods: We reviewed the histopathological findings and molecular profiling of patients with PNETtreated in our institution. The clinical courses were followed by medical records.

Results: We had 5 patients diagnosed as PNET. There were 3 boys and 2 girls with the median ageof 3‐year‐old. All tumors were located on supratentorial brain and received the treatmentincluding surgery, radiation therapy, and chemotherapy. Histopathologically they werediagnosed CNS neuroblastoma in 2 patients, ETMR in 1, and CNS embryonal tumor, NOSin 2. Amplification of C19MC was only detected in ETMR. The follow up period was 20 to62 months and clinical outcome was following; 2 patients were complete remission, other 2patients were dead of disease, and 1 patient was progressive disease status.

Conclusion: In this study, we reviewed the clinical courses of patients diagnosed as PNET previously. Developing technology of molecular analysis revealed the tumor characteristic and mightbe led to the appropriate treatment in the future.

Differences in clinical course of group‐A and group‐B posterior fossa ependymoma (PFA, PFB) as defined by H3K27me3 immunohistochemical analysis

Ushio Yonezawa¹; Fumiyuki Yamasaki¹; Takeshi Takayasu¹; Motoki Takano¹; Masako Yoshihiro¹; Vishwa J. Amatya²; Yukio Takeshima²; Kazuhiko Sugiyama³; Kaoru Kurisu¹

¹Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; ²Department of Pathology, Institute of Biomedical and Health Sciences, Hiroshima University; ³Department of Clinical Oncology & Neuro‐Oncology Program, Hiroshima University

Introduction: Posterior fossa ependymoma is classified as PFA and PFB based on underlying genetic/mutational characteristics, and PFA is reported to have poor prognosis compared to PFB. Recently, immunohistochemical findings of negative H3K27me3 have been reported to suggest PFA and attracted the attention as a surrogate marker. We classified our cases into PFA and PFB guided by immunohistochemical staining results of H3K27me3 and examined their clinical course. Between 1999 and 2018, 17 cases of posterior fossa ependymoma were treated at our institute. Negative immunostaining for H3K27me3 was classified as PFA, and positive as PFB. Nine cases were classified as PFA and eight as PFB. The average age of the PFA group was 6.7 years‐old, 4 males, 5 females, pathological diagnosis was ependymoma in 5, and anaplastic ependymoma in 4 cases. The median follow‐up period was 50 months, recurrence was confirmed in 5 cases (56%), progression free survival (PFS) was 27.6 months. Three of the 5 patients who relapsed died (33%), and the overall survival (OS) was 50 months. The mean age of the PFB group was 47 years, 4 males and 4 females, the pathological diagnosis was ependymoma in 6, and the anaplastic ependymoma in 2 cases. The median follow‐up period was 111 months, recurrence was observed in 2 cases (25%), PFS was 98 months and all patients were alive during the period of this research. Immunohistochemical results of H3K27me3 correlated with prognosis, implying the possibility of it being a surrogate marker of posterior fossa ependymoma.