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The most recurrent fusion of central nervous system high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) is MN1 rearrangement. Here, we report the case of a 36-year-old man with spinal cord astroblastoma showing Ewing Sarcoma breakpoint region 1/EWS RNA-binding protein 1 (EWSR1)-BEN domain-containing 2 (BEND2) fusion. The patient presented with back pain, gait disturbance and dysesthesia in the lower extremities and trunk. Magnetic resonance imaging showed an intramedullary tumor at the T3-5 level, displaying homogeneous gadolinium enhancement. Partial tumor removal was performed with laminectomy. Histological examinations demonstrated solid growth of epithelioid tumor cells showing high cellularity, a pseudopapillary structure, intervening hyalinized fibrous stroma, and some mitoses. Astroblastoma was diagnosed, classified as HGNET-MN1 by the German Cancer Research Center methylation classifier. MN1 alteration was not detected by fluorescence in situ hybridization (FISH), but EWSR1-BEND2 fusion was detected by FISH and RNA sequencing. Previously, a child with EWSR1-BEND2 fusion-positive spinal astroblastoma classified as HGNET-MN1 was reported. In conjunction with that, the present case provides evidence that EWSR1-BEND2 fusion is identified in the entity of HGNET-MN1. Taken together, the BEND2 alteration rather than MN1 may determine the biology of a subset of the central nervous system HGNET-MN1 subclass.

Rosette-forming glioneuronal tumors (RGNTs) are benign WHO grade 1 tumors that occur in the ventricular system, particularly the fourth ventricle. RGNTs and dysembryoplastic neuroepithelial tumors (DNTs) are both categorized as neuronal and mixed neuronal-glial tumors and may be difficult to distinguish. Coexistence of the two tumor types has been reported. Here, we report a pediatric case of RGNT with DNT-like features showing intraventricular dissemination. The tumor occurred in the medial temporal lobe and presented with specific pathological glioneuronal elements including floating neurons, which are typical in DNTs, but was diagnosed as RGNT because of the presence of neurocytic rosettes. Genetic analysis detected fibroblast growth factor receptor 1 internal tandem duplication (FGFR1-ITD) of the tyrosine kinase domain, which was previously reported to be specific for DNT. RGNTs with FGFR1-ITD may show atypical clinical presentation and pathological features.

A 5-year-old girl presented with headache and vomiting. Head computed tomography and magnetic resonance imaging showed a right frontal lobe tumor with marked calcification. The patient underwent resection surgery with suspicion of anaplastic ependymoma, and the tumor was gross totally removed. Pathological examination revealed areas of dense tumor cells with a high nucleocytoplasmic ratio and myxoid areas consisting of tumor cells with a round-shaped nucleus and eosinophilic cytoplasm. Perivascular pseudorosette, necrosis, circumscribed growth, and microcalcification were also observed. Immunohistochemistry demonstrated negative staining for glial fibrillary protein and epithelial membrane antigen. Diagnosis of a high-grade neuroepithelial tumor (HGNET) with BCL6 corepressor (BCOR) alteration was made based on pathological findings and internal tandem duplication in the exon 15 of BCOR. Although calcification on radiological and pathological examination is not typical, it would be essential to recognize that calcification could appear in HGNET-BCOR.

To clarify the morphologic spectrum and molecular profiles of hybrid schwannoma/perineurioma (HSP), we investigated 15 tumors clinicopathologically and cytogenetically. HSP was classified into 2 morphologic types: mixed cellular and combined tumor types. The former comprising of 14 tumors mostly arose in the subcutaneous tissue of the extremities and the trunk of middle-aged adults. They were well-circumscribed and composed of elongated spindle-shaped tumor cells arranged in storiform and whorl patterns. Immunostaining revealed a mixed cellular proliferation of S-100 protein-positive and SOX10-positive Schwann cells and epithelial membrane antigen-positive, claudin 1-positive, and GLUT1-positive perineurial cells. During follow-up, no tumors were found to have recurred in any cases. In contrast, in the combined tumor type arising in the mediastinum of a young male with neurofibromatosis type 2, the intraneural perineurioma-like areas, characterized by small whorl-like structures, were present in plexiform schwannoma-like areas. No recurrence was noted in the case. Molecular analyses (array comparative genomic hybridization and fluorescence in situ hybridization) revealed LOH 22q in 2 tumors of 5 studied: one each of the mixed cellular and combined tumor types. Although the same diagnostic term, HSP, has been applied to both mixed and combined types, they should be separated from each other.

A 6-year-old female was incidentally found to have a brain tumor. Magnetic resonance imaging (MRI) demonstrated a gadolinium-enhanced mass in the left parietal lobe. We performed gross total resection with the assistance of fluorescent guidance by 5-aminolevulinic acid (5-ALA). A histological examination of the tumor specimen showed well-differentiated astroblastic features with focal anaplasia. Fluorescence in situ hybridization (FISH) revealed meningioma 1 (MN1) gene alteration and supported our diagnosis. She received local radiotherapy and oral temozolomide followed by maintenance temozolomide chemotherapy, and the tumor was well controlled without any neurological deficit for 27 months. Our case is considered to be valuable since it describes a patient who is diagnosed to have a well-differentiated astroblastoma with both focal anaplastic features and MN1 gene rearrangement. A larger study is warranted to establish evidence supporting the diagnosis and treatment of astroblastoma with molecular characteristic features. MN1 alteration will be a diagnostic marker for astroblastoma in the future.

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant tumors of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (rarely) BRG1. Most AT/RT are identified as primary tumors; however, rare AT/RT or INI1-deficient RTs arising from other primary tumors have been reported. Here, we report 3 cases of hitherto unclassifiable low-grade tumors with loss of INI1 nuclear expression, for which we propose the designation of central nervous system low-grade diffusely infiltrative tumors with INI1 deficiency (CNS LGDIT-INI1), 2 of which progressed to secondary RT. All 3 CNS LGDIT-INI1 exhibited a similar histology: diffusely distributed small tumor cells with round to oval or irregular nuclei and scant cytoplasm were admixed with degenerative neurons and large reactive astrocytes in an edematous, myxoid, or collagenous background. Mitotic figures were absent. Immunohistochemistry revealed that the tumor cells in all 3 CNS LGDIT-INI1 and 2 RT were negative for INI1. Genetically, total or partial homozygous deletions of the INI1 gene were detected in all CNS LGDIT-INI1 and RT excluding 1 CNS LGDIT-INI1 without sufficient DNA quality and quantity. Despite the loss of INI1 expression, these low-grade lesions were clearly distinguishable from AT/RT by their low proliferative activity, diffusely infiltrative growth pattern, and lack of rhabdoid cells and polyphenotypic immunoreactivity. In conclusion, CNS LGDIT-INI1 may represent a rare group of tumors that are clinically indolent but have a high propensity to progress to RT.

The CIC-DUX4 translocation is the most common genetic alteration of small round cell sarcomas without EWSR1 rearrangement. These "Ewing-like sarcomas" usually occur in peripheral soft tissues, and rare primary central nervous system (CNS) tumors have been described. We report a rare case of primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation. A 23-year-old man presented with weakness in the extremities. Magnetic resonance imaging revealed a large intramedullary tumor spanning C3-C5 with heterogeneous enhancement following gadolinium administration. Histologically, most of the tumor displayed dense myeloid proliferation composed of medium- to slightly small-sized primitive cells. Postoperatively, he received local adjuvant radiation therapy without tumor progression for 10 months. Target RNA sequencing analysis revealed the CIC-DUX4 fusion gene. Methylation array analysis resulted in a diagnosis of "methylation class CNS Ewing sarcoma family tumor with CIC alteration". Although this tumor lacked characteristic histological features such as lobular structures in association with desmoplastic stroma, relatively uniform nuclei with prominent nucleoli and eosinophilic cytoplasm, which are often found in CIC-rearranged sarcomas of soft tissue, were identified. Recently, many CNS and soft tissue tumors require genetic analysis for precise diagnosis. To consider certain molecular testing, careful histological examination is essential.

Dysembryoplastic neuroepithelial tumors (DNTs) are regarded as benign glioneuronal neoplasms because of their excellent outcomes; however, rare DNTs show malignant transformation. We herein described a case of DNT showing malignant transformation. The patient had intractable epilepsy caused by a tumor at 1 year of age and partial resection was performed. After surgery, the residual tumor showed regrowth and surgery was performed again at 4 years of age. The resected tumor showed the typical histological features of DNT, such as specific glioneuronal elements and alveolar structures. Tumor regrowth was detected again at 6 years of age, and the patient underwent gross total resection. Histologically, the tumor was composed of a high-grade glial component mixed with atypical neuronal cells, and the diagnosis of an anaplastic glioneuronal tumor was made. Genetically, DNT and the anaplastic glioneuronal tumor both shared a copy number gain of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1), as demonstrated by multiplex ligation-dependent probe amplification (MLPA), corresponding to internal tandem duplication (ITD). A frequent FGFR1-ITD in DNT was previously reported. To the best of our knowledge, an identical mutation between primary and transformed DNT has not yet been demonstrated by MLPA.

Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

We report a histological and genetic study of concurrent oligodendroglioma and a microscopic pleomorphic xanthoastrocytoma (PXA)-like lesion in a 48-year-old male. He presented with generalized seizure, and magnetic resonance imaging revealed a nonenhanced left frontal lobe mass suggesting low-grade glioma. The patient underwent craniotomy and tumor resection. Histopathological examination of the surgical specimen showed an oligodendroglioma with a PXA-like element; the latter measured 0.9 mm and occupied a Virchow-Robin space of the superficial cortex. The whole tumor had no elevated mitotic activity, microvascular proliferation or necrosis. Each component was immunohistochemically isocitrate dehydrogenase (IDH1)-R132H positive, p53 negative and ATRX positive. Genetic analyses clarified identical IDH1 G395A mutation, promoter C228T mutation and 1p/19q codeletion in both elements. Careful integration of histology and telomerase reverse transcriptase (TERT) molecular parameters revealed that this case was an oligodendroglioma showing PXA-like features, rather than a collision tumor. This case provides further insights into the gliomagenesis.

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (extremely rarely) BRG1. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding INI1 alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic INI1 inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary "AT/RT" as most of the reported cases were.

Management of pregnant women with brain tumors necessitates difficult decision-making especially for estimating or preventing its intratumoral hemorrhage. A 26-year-old, 19-week pregnant woman complaining of headache and vomiting was admitted to our hospital. Magnetic resonance imaging (MRI) revealed hydrocephalus and a mass lesion without contrast enhancement extending from the left thalamus. To resolve severe symptoms, a ventriculoperitoneal shunt was inserted, and a biopsy was taken via the right ventricle. Pathological examination suggested diffuse or pilocytic astrocytoma, but subsequent genetic analysis revealed the diagnosis of midline glioma with H3-K27M mutation. The patient opted not to terminate the pregnancy, and MRIs conducted every four weeks revealed no change in tumor aspect. The patient delivered a healthy baby by cesarean section, and postpartum day 1 was uneventful. However, she was found in a coma due to a massive intratumoral hemorrhage on postpartum day 2 and died 3 weeks after the hemorrhage. This is the first case report of diffuse midline glioma with H3-K27M mutation in a pregnant woman followed by fatal hemorrhage. It highlights the necessity of careful clinical management and frequent neuroimaging during the entire perinatal period, even if the tumor has hypovascularity or low proliferative potential on radiological or pathological findings.

Here, we report a rare case of anaplastic pleomorphic xanthoastrocytoma (PXA) associated with an H3G34 mutation. A 12-year-old male presented with loss of appetite, vomiting, headache, and a generalized seizure, and CT revealed a 9.0 cm left frontal lobe mass with some septal walls and a localized high-density area suggestive of hemorrhage or calcification, causing severe midline shift. He emergently underwent subtotal resection and the tumor was morphologically diagnosed as anaplastic PXA. DNA sequencing identified an H3F3A G34R mutation and a TP53 R273H mutation, and immunohistochemically, ATRX nuclear expression was lost. In CNS tumors, H3G34 mutations are essentially detected in glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors. Those tumors most likely comprise a single biological entity (high-grade glioma with H3G34 mutation) because of no significant difference in molecular profiling and prognosis between GBM and PNET morphologies. To our knowledge, our present case is the first one of anaplastic PXA associated with an H3G34 mutation, and whether it biologically corresponds to "high-grade glioma with H3G34 mutation" needs further studies.

Gastric hyperplastic polyps are common and generally regarded as benign lesions, whereas gastric adenocarcinomas infrequently occur from gastric hyperplastic polyps. Although gastric hyperplastic polyps have received a lot of attention because of their association with malignant transformation, it remains unclear whether gastric hyperplastic polyps are neoplastic lesions that have sporadic genetic changes similar to colorectal hyperplastic polyps. We performed genome-wide analyses of two gastric adenocarcinomas with hyperplastic polyp components. The interface between "adenocarcinoma" and "hyperplastic polyp" components was fairly sharp, and the adenocarcinoma components had copy number alterations and TP53 mutations, whereas the hyperplastic polyp components had only single nucleotide polymorphisms, which were also found in adenocarcinoma components. We did not detect any somatic changes in the hyperplastic polyp components, even in genome-wide analyses, which was in contrast to the adenocarcinoma components. However, due to the small number of cases examined herein, further genetic analyses of more cases are needed.

Astroblastoma is an extremely rare brain tumor that has recently attracted attention owing to its association with MN1 gene alteration. However, its long-term clinical course remains unclear. We report a late recurrence of MN1-altered astroblastoma with unique pathological findings. A 24-year-old woman presented with seizures due to a left frontal lobe tumor. Gross total resection (GTR) was achieved, and the diagnosis was MN1-altered astroblastoma, which presented cell wrapping, i.e., presence of tumor cells enveloping one another. She received local radiotherapy (50 Gy). However, the tumor recurred after 12 years, and its size increased rapidly. The second surgery achieved GTR and confirmed increasing anaplasia. The patient was tumor-free for 1 year without any neurological deficits. This case implies the importance of long-term follow-up of MN1-altered astroblastoma. The pathological significance of cell wrapping in this case is unclear, but it may be associated with MN1-altered astroblastoma and should be noted in future cases.

Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low- to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95-NCOA1 or -NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95-RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.

Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.

Broncho-biliary fistula (BBF) is a rare but severe disorder defined as abnormal communication between the biliary system and bronchial tree. Cases of BBF have occasionally been reported, but no standard treatment has been established. We report two cases of BBF that developed after the treatment of hepatocellular carcinoma (HCC) and reviewed the relevant literature. Case 1, a man in his early eighties was diagnosed with BBF 4 months after undergoing surgical resection for HCC (diameter, 7 cm; location, segments 4 and 5). Percutaneous drainage and endoscopic nasobiliary drainage (ENBD) improved BBF without recurrence for more than a year. Case 2, a woman in her late sixties was diagnosed with BBF after percutaneous radiofrequency ablation for HCC. Although the BBF was treated with ENBD, bronchial occlusion, and percutaneous transhepatic portal vein embolization, these treatments were unsuccessful and the patient died. Although non-invasive treatments have been developed, refractory BBF still exists. The prediction of BBF and the development of more effective treatments are necessary to improve outcomes.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

Desmoplastic myxoid tumor (DMT), SMARCB1-mutant is a recently proposed brain tumor that occurs in the pineal region of adults. This tumor is characterized by desmoplastic stroma and various degrees of myxoid matrix. Tumor cells with low-grade morphology show polyphenotypic immunoreactivity, and rhabdoid cells are rare. We herein present a case with some uncommon features such as no myxoid stroma and slightly elevated proliferating activity. To date, knowledge on the variety of SMARCB1/INI1-deficient tumors of the central nervous system is gradually increasing, encompassing highly aggressive to slow-growing varieties. DMT, SMARCB1-mutant seems to be relatively benign, but careful attention is necessary because SMARCB1/INI1 deficiency is generally a genetic signature of concern.

Background Hepatocellular adenoma (HCA) is conventionally considered a rare benign liver tumor, but advanced studies have revealed that HCA is heterogeneous, and may include a type that is prone to malignant transformations. Differentiation between well-differentiated hepatocellular carcinoma and focal nodular hyperplasia is necessary to diagnose hepatocellular adenoma through imaging; however, the tumor marker of hepatocellular carcinoma, protein induced by vitamin K absence, or antagonist II (PIVKA-II), is rarely positive in hepatocellular adenoma. Case presentation A 44-year-old woman presented to our hospital with complaints of loss of appetite and weight loss. Multidetector row computed tomography revealed a liver tumor (diameter, 80 mm) that was enhanced in the arterial phase. Her serum PIVKA-II level was very high (3327 mAU/mL). Based on the enlargement of the mass and the results of the diagnostic imaging, hepatocellular adenoma or hepatocellular carcinoma was suspected, and we considered the possibility of a malignant transformation due to the high level of serum PIVKA-II; thus, we performed hepatectomy. Histological examination showed brown pigment deposition in the hepatocytes, which was determined to be lipofuscin granules. Based on immunohistochemical findings, the diagnosis was unclassified hepatocellular adenoma. Immunohistochemical examinations revealed that the adenoma cells in the tumor were positive for PIVKA-II. Her serum PIVKA-II level returned to normal after the resection. Conclusions We present a case of unclassified hepatocellular adenoma with brown pigment deposition and elevation of serum PIVKA-II level. For the differentiation of liver tumors with high levels of PIVKA-II and hypervascular mass, hepatocellular adenoma should be considered.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.

Astroblastoma is a rare glial neoplasm that occurs mostly in the cerebral hemisphere of children, adolescents and young adults. Although astroblastic perivascular pseudorosettes are unique histopathology of this neoplasm, diagnosis is usually challenging. Recently, it was discovered that the meningioma 1 gene (MN1)-altered pediatric central nervous system high-grade neuroepithelial tumors are actually astroblastomas. This case report presents a rare brainstem astroblastoma, with an unusual immunoprofile: negative for glial fibrillary acidic protein and oligodendrocyte transcription factor 2, but with a robust expression of pancytokeratin and epithelial membrane antigen. The diagnosis was confirmed based on the detection of MN1 rearrangement in a fluorescence in situ hybridization study, in addition to typical histopathology. Here we discuss the diagnostic pitfalls and unclear grading system along with a literature review.

A 40-year-old man was admitted to our hospital because of disorientation and mild left-sided weakness. Radiological examination revealed a solid and cystic tumor in the right temporal lobe, and total resection was performed. Histologically, the tumor was composed mainly of low-grade gangiloglioma and had some high-grade glial components with focal necrosis and microvascular proliferations. In the high-grade component, there were epithelioid cells with round cytoplasm and eccentric nuclei. The high-grade area with epithelioid cells was intermingled within the low-grade area, which suggests that epithelioid cells were an anaplastic transformation of ganglioglioma. The epithelioid cells were histologically similar to neoplastic cells of epithelioid glioblastoma (E-GBM), a rare aggressive variant of isocitric dehydrogenase wild-type glioblastoma. A BRAF V600E mutation, frequently observed in E-GBM, was detected in both the ganglioglioma and epithelioid cell components. The epithelioid cells were mitotically active, which suggests that if the surgery was delayed, the histological appearance might have eventually evolved into E-GBM. Indeed, a case of pleomorphic xanthoastrocytoma which transformed into E-GBM after a long latency was reported elsewhere. This is the first report to describe focal epithelioid cells in anaplastic ganglioglioma.

A 51-year-old man presented with a 2-week history of malaise. MRI revealed a large solid and cystic lesion with ring enhancement measuring 6.5 cm in diameter in the right frontal lobe. Histologically, the tumor consisted of various components: diffuse growth of atypical astrocytic cells consistent with glioblastoma, fascicular proliferation of atypical spindle cells such as fibrosarcoma, clusters of primitive neuronal cells, and foci of ependymal cells. The sarcomatous component also focally exhibited chondroid and osteoid differentiation. Immunohistochemically, tumor cells in the primitive neuronal component were immunoreactive for synaptophysin and CD56. The spindle cells were immunopositive for Slug and Twist, regulators of epithelial-mesenchymal transition. Direct DNA sequencing demonstrated C228T mutation in the TERT promoter in astrocytic, sarcomatous and primitive neuronal components, suggesting their identical origin. Although a few cases of gliosarcoma with primitive neuronal differentiation have previously been described, the finding that neuronal, glial and sarcomatous components share an identical mutation of the TERT promoter has not been reported. The tumor recurred at the original site 11 months after the first surgery. Interestingly, the recurrent tumor was composed exclusively of a glioblastomatous component, unlike past cases of recurrent gliosarcoma.

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. In this study, 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. 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. 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.

Epithelioid glioblastoma (E-GBM) is a rare aggressive variant of IDH-wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. 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. To better understand associations between E-GBM and the lower-grade lesions, we undertook a histological and molecular analysis of 14 E-GBM, 10 of which exhibited lower-grade glioma-like components (8 E-GBM with co-existing diffuse glioma-like components, 1 E-GBM with a co-existing PXA-like component and 1 E-GBM with a pre-existing PXA). Molecular results 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. In conclusion, E-GBM frequently exhibit BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions and these alterations tend to coexist in E-GBM. Taken together with the facts that only one PXA preceded E-GBM among these lower-grade lesions, and that co-occurrence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions have been reported to be rare in conventional lower-grade diffuse gliomas, the diffuse glioma-like components may be distinct infiltrative components of E-GBM, reflecting intratumoral heterogeneity.

Radiation-induced glioma (RIG) is a rare secondary glioma. The tumors morphologically resemble their sporadically arising counterparts. Recently, the WHO classification of tumors of the central nervous system was revised to incorporate molecular biomarkers together with classic histological features. The status of molecular biomarkers in RIG, however, remains unclear. The objective of this study was to investigate if commonly accepted glioma-specific biomarkers are relevant in RIGs. Among 269 gliomas diagnosed as WHO grade 2, 3 and 4 in our institution, four were diagnosed as RIGs. Immunohistochemical (IHC) staining for isocitrate dehydrogenase 1 (IDH1), p53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and H3K27M, and direct DNA sequencing of IDH1/2, telomerase reverse transcriptase (TERT) promoter, Histone H3.3 (H3F3A) and B-Raf (BRAF) genes was performed. All tumor specimens were IDH1-, p53- and H3K27M-negative. The nuclei of tumor cells in all cases exhibited positive staining for ATRX. In direct DNA sequencing analysis, no IDH1, IDH2, TERT promoter, H3F3A or BRAF mutations were found in any of the cases. Our findings suggest that these characteristic glioma-associated molecular mutations may be rare events in RIGs. More RIGs need to be tested for analysis of molecular biomarkers to clarify the clinical and histopathological spectra of this tumor.

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive tumors of the central nervous system that predominantly affect infants. Although adult AT/RT are rare, accumulated cases have revealed adult-specific AT/RT in the sellar region. Twelve previously reported cases of sellar AT/RT exclusively occurred in adult females, suggesting biological differences from conventional infant AT/RT. We herein investigated a series of 6 sellar AT/RT for histopathologic features, the molecular status of the INI1/SMARCB1 gene, and clinical courses. All 6 cases were adult females, ranging in age from 21 to 69 years old. Tumors were histologically characterized by a hemangiopericytoma-like stag-horn vasculature within a dense, diffuse proliferation of jumbled cells and a small number of scattered rhabdoid cells. This vascular pattern is not a common finding in AT/RT and appears to be a characteristic histology of sellar AT/RT. Biallelic alterations in the INI1 gene were identified by fluorescence in situ hybridization, direct sequencing, and multiple ligation-dependent probe amplification analyses in 4 of the 5 cases analyzed. Three of the 4 cases harbored 2 different mutations, presumably on different alleles (compound heterozygous mutations), and 1 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. Sellar AT/RT represent a clinicopathologically and possibly genetically distinct variant of AT/RT showing a characteristic demography, different patterns of INI1 alterations, and a histology featured by a unique vasculature.

Dentatorubral-pallidoluysian atrophy (DRPLA), one of the polyglutamine diseases, has not been reported in combination with ganglioglioma (GG). Herein, we report an autopsy case of a 72-year-old man with DRPLA with a small GG component harboring neurofibrillary tangles (NFTs) and polyglutamine aggregates. NFTs, cytoplasmic accumulations of hyper-phosphorylated tau, are mainly observed in Alzheimer's disease (AD) and other tau-associated neurodegenerative disorders. NFTs can also be present in normal aging, and are occasionally observed in low-grade central nervous system (CNS) neoplasms such as GG. In the present case, whole brain examination demonstrated widespread deposition of polyglutamine aggregates, including GG, whereas NFTs were restricted to the GG component. In addition, no other AD or aging-related neuropathological structures were detected throughout the CNS. These findings may provide us with clues to elucidate the pathogenetic mechanisms that neuronal neoplasms may have to develop NFTs regardless of aging, and that polyglutamine may accumulate in neoplastic neurons in polyglutamine disease.

A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta-1a treatment was admitted to a local hospital for severe icterus and liver injury. She was transferred to our university hospital because fulminant hepatitis (FH) was suspected. She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy. On hospital day 6, she died from liver failure despite intensive care. An autopsy revealed histological findings consistent with FH. Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases.

ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P

BACKGROUND Choroid plexus tumors (CPT) include choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Because of their rarity, limited data are available on the current status of treatment and outcomes for pediatric CPTs. METHOD We retrospectively reviewed clinical information on patients with CPT patients aged between 0 and 30 years at diagnosis and were treated in 8 institutions in Japan. RESULTS Of forty-two cases initially diagnosed as CPT, 18 cases were reviewed by central pathologists. As a result, the diagnosis of CPC or aCPP in five cases were changed to other tumors including AT/RT and astroblastoma. The remaining 37 cases were subjected to analysis. Median age at diagnosis was two years (0 to 25) and the mean follow-up period was seven years. All 26 patients with CPP (n=20) or aCPP (n=6) underwent gross-total resection without adjuvant therapy. Of them 24 patients are alive without recurrence. Four patients of patients with CPC (n=11) died of cancer. Five patients including three patients experienced local relapse, achieved complete remission after resection of tumor plus chemoradiotherapy. All three patients with dissemination of CPC at diagnosis or relapse died of the disease. At least three patients were diagnosed with Li-Fraumeni syndrome: one died of medulloblastoma and one patient developed osteosarcoma. CONCLUSION Compared with the excellent prognosis of CPP, the survival rates for CPC, especially disseminated CPC are unsatisfactory. Our results also underline the importance of considering genetic testing of TP53 for patients with CPC.

Epithelioid glioblastoma is a rare subtype of glioblastoma, but the coexistence of a sarcomatous component is even rarer. An 80-year-old woman was admitted to our hospital with somnolence. Magnetic resonance imaging revealed a cystic lesion with a solid component in the left temporal-parietal lobe. Histopathological examination of the resected tumor revealed three components; namely, typical glioblastoma, sarcomatous and epithelioid components at a ratio of about 5:3:2. All components were immunohistochemically positive for vimentin and mutated BRAF (V600E) and showed focal expression of glial fibrillary acidic protein and cytokeratin AE1/AE3, but they were negative for isocitrate dehydrogenase 1. Genetic analysis revealed that both the sarcomatous and epithelioid components harbored BRAF T1799A (V600E) mutation and homozygous deletion of cyclin-dependent kinase inhibitor 2A/B. We diagnosed this tumor as epithelial glioblastoma with a sarcomatous component. Our results indicate that even when the epithelial component is not dominant, immunohistochemical and genetic investigation of BRAF mutations is useful for the diagnosis of glioblastoma subtypes. In particular, although the prognosis of epithelial glioblastoma is poor, potentially effective targeted therapies for BRAF V600E-mutated tumors are available.

Glioneuronal tumor (GNT) is a rare central nervous system neoplasm composed of glial and neuronal components. Making the specific diagnosis of GNT can be challenging due to histopathological and genetical similarities among some GNTs and low-grade gliomas. We report a case of GNT with rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, and pilocytic astrocytoma-like morphology harboring FGFR1 mutation. A 16-year-old female presented with absence seizures. Magnetic resonance imaging revealed a right temporal lobe mass with multinodular enhancement by gadolinium administration. The tumor was mostly composed of oligodendrocyte-like cells (OLCs) with variable perinuclear haloes. Abundant Rosenthal fibers and eosinophilic granular bodies were identified. Neither mitotic figures nor areas of necrosis were seen. Focal neurocytic rosette features, involving ring-like arrays of OLCs around eosinophilic cores, were observed. Direct sequencing showed a missense mutation in FGFR1 K656E, whereas FGFR1 N546K, PIK3CA, and BRAF V600E were intact. KIAA1549-BRAF fusion was not detected by fluorescence in situ hybridization analysis.

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3–46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare malignant neoplasms of the CNS that preferentially affect young children. We herein report an adult case of AT/RT surviving for more than 5 years with the residual tumor. The patient, a 24-year-old man at onset, presented with a contrast-enhancing mass lesion in the left occipital lobe, and underwent partial tumor resection. Histologically, the tumor was predominantly composed of long spindle cells exhibiting nuclear palisading and perivascular pseudorosettes, which appeared to mimic mesenchymal, ependymal and Schwann cell tumors. A small number of isolated rhabdoid cells did not initially attract attention, and a tentative pathological diagnosis of a malignant mesenchymal tumor was made. In a later examination focusing on the small areas of rhabdoid cells, the extensive loss of the nuclear expression of INI1 was detected in all areas. Diffuse staining with vimentin and focal immunoreactivity for epithelial membrane antigen and alpha smooth muscle actin were observed not only in AT/RT foci, but also in spindle cell areas. Thus, polyphenotypic immunoreactivity was evident. Fluorescence in situ hybridization revealed a homozygous deletion of chromosome 22q covering the INI1 locus. Histopathological differences between infant and adult AT/RTs currently remain unclear. In the case of a malignant adult brain tumor showing a hardly classifiable morphology and immunophenotypic diversity, an analysis of the INI1 status may contribute to an accurate diagnosis.

INTRODUCTION Since 2016, the Japan Children’s Cancer Group (JCCG) has established a nationwide network that prospectively provides pathological review and molecular analysis. METHODS Patients who were diagnosed with brain tumors between ages 0 and 29 were eligible. The central office at National Center for Child Health and Development served as a hub for the hospitals involved and institutions conducting pathological and molecular analysis, and managed the patients’ clinical information and tumor samples. Histopathology of all cases were centrally reviewed. Routine non-NGS based analyses were conducted based on histological diagnosis and included pyrosequencing for glioma-associated hot spot mutations and PFA/PFB classification for ependymoma, RT-PCR for RELA fusion and BRAF fusion, and nanostring for subgrouping medulloblastoma. In selected cases, methylation analysis, RNA sequencing and exon sequencing of 93 genes were performed in selected cases. RESULTS In total, 985 cases were registered to this study in four years. Frozen samples were collected from approximately 80% of cases. The number increased from 152 in 2016 to 326 in 2019. They includes glioma (n=268), medulloblastoma (n=161), ependymoma (n=103), germ cell tumor (n=93), ATRT (n=29) and others. In 55 % of the glioma cases, at least one abnormality was detected by the routine analysis. The detailed analysis for atypical cases identified targetable alternations. DISCUSSION: This nationwide central diagnostic system has now been well established. Current issues and future prospective of the system will be discussed.

Molecular tests have now become an essential part of clinical management of pediatric brain tumor patients. We have established a central diagnosis system for pediatric brain tumors in Japan to provide standardized molecular diagnostic service. Tumor specimen are accepted from centers participating Japan Children’s Cancer Group (JCCG). The JCCG Datacenter at National Center for Child Health and Development (NCCHD) manages all patients’ specimen and information. Histology is centrally reviewed at Gunma University Hospital. Molecular tests are performed at either Osaka National Hospital (medulloblastoma), Gunma University Hospital (ETMR) or National Cancer Center (all the others). Medulloblastomas are classified by expression profiling using the nanostring technology, and mutations of CTNNB1, TP53 and TERT determined. Gliomas are examined for mutations of BRAF, H3F3A, HIST1H3B, FGFR1, IDH1/2 and TERT using pyrosequencing, as well as for BRAF fusion by RT-PCR as necessary. Supratentorial ependymomas are examined for the presence of RELA fusion by RT-PCR, and posterior fossa ependymomas are classified as PFA or PFB by DNA methylation analysis. Those tumors negative for the routine analyses may be subjected to RNA sequencing or targeted sequencing for 93 genes known to be mutated in brain tumors. As of August 2017, over 200 tumors have been molecularly diagnosed and the integrated diagnosis reported to each center. Our system is affordable utilizing minimum amount of high throughput technologies, and will hopefully improve the standard of diagnosis for pediatric brain tumors.

Astroblastoma is a rare tumor that is thought to occur exclusively in the cerebrum. To the authors’ knowledge, no cases of spinal cord astroblastoma have been reported. A 20-year-old woman presented with numbness in her legs. MRI demonstrated a 2-cm intramedullary enhancing lesion in the spinal cord at the T-1 level. The patient declined to undergo resection of the tumor because she was able to walk unassisted; however, she returned for surgery 1 month later because she had developed paraplegia with bladder and rectal dysfunction, and MRI showed enlargement of the tumor. Intraoperatively, the border between the tumor and normal tissue was poorly defined. Biopsy samples were obtained for histopathological examinations, and a diagnosis of astroblastoma with a Ki-67 index of 5% was made. Considering the rapid tumor growth on MRI and remarkable deterioration in her symptoms, the patient was treated with a combination of radiation therapy, temozolomide (TMZ), and bevacizumab. After completion of the combined treatment, she was able to move her toes, and oral TMZ and bevacizumab injections were continued. Six months later, definite tumor shrinkage was identified on MRI, and the patient was able to stand up from a wheelchair without assistance and walk by herself. No therapeutic regimens for residual astroblastoma are established; however, in this case the authors’ therapeutic strategy was successful in treating the spinal cord astroblastoma.

Neural components in mature teratomas are common and the general assumption is that they are quite similar to those in the mature central nervous system (CNS). We investigated 44 ovarian teratomas by immunohistochemistry to determine cellular and structural immaturity of neural elements. Most teratomas contained cells differentiating into astrocytes positive for nestin, a neural stem cell marker. These nestin-positive astrocytes generally co-expressed glial fibrillary acidic protein-delta, an immature astrocyte marker. Olig2-positive cells were randomly scattered. Areas comprising cells that differentiated into neurons were positive for NeuN and synaptophysin. The border between white and gray matter was ill-defined and more NeuN-positive cells were distributed in areas that were positive for myelin basic protein, indicating that the distribution of neurons and glial cells was disturbed. Peripheral nerve bundles positive for Schwann/2E, an antigen specific for myelinating Schwann cells, were mixed within CNS-like tissues. These results show that apparently mature teratomas are not in fact mature, at least in terms of neural elements, as they harbor immature cells and structural abnormalities. The neural elements of surgically resected teratomas might represent a premature state of the human CNS, and thus be potentially useful for studies of developmental neurobiology as well as gliomagenesis.

The pathogenesis of sarcomatous component in spindle cell carcinoma (SpCC) of the esophagus is unclear. To investigate the involvement of epithelial-mesenchymal transition (EMT) in sarcomatous differentiation, we performed immunohistochemistry for Slug, Twist, ZEB1, and ZEB2, transcription factors associated with EMT and E-cadherin, in 14 cases of SpCC of the esophagus. In order to verify the neoplastic nature of sarcomatous components, TP53 mutation status and protein expression were examined in each case. Nuclear ZEB1 expression was extensive in the sarcomatous component, greater than invasive front of carcinoma components (P < 0.0001). Membranous E-cadherin expression was mostly lost in sarcomatous cells in all cases (P < 0.0001). The p53 expression pattern was almost concordant between the two areas in all cases. TP53 mutation analysis revealed that seven cases harbored identical mutations in both components. One case had mutations only in the sarcomatous component. It is noteworthy that none of them harbored mutation in exon 5, unlike conventional esophageal squamous cell carcinoma. These findings show that ZEB1 are widely expressed in the sarcomatous area of SpCC of the esophagus, suggesting the involvement of EMT. The avoidance of exon 5 in terms of TP53 mutation may also be a feature of the tumor.

A 12-year-old girl presented with a generalized convulsion. She had regularly consulted pediatricians for an adjustment disorder over the course of 2 years and had experienced a transient episode of unconsciousness without convulsion 5 months earlier. A mental status examination revealed depressed affect, but general physical and neurological examinations were unremarkable. Computerized tomography scans showed a cystic lesion with calcifications in the left temporal lobe (Fig. 1a). A 3.2 9 2.2 cm solid tumor nodule with a unilocular cyst involving the left middle temporal gyrus was detected by magnetic resonance imaging (MRI). The solid tumor nodule was heterogeneously hyperintense on T2-weighted, T1-weighted, and FLAIR images and isointense on diffusion-weighted images with a heterogeneous contrast enhancement (Fig. 1b– d). The patient underwent surgery because of poor seizure control with anticonvulsant drugs, and the nodule was totally resected. The thickened cyst wall was partially removed to preserve the essential language center of the brain. Intraoperative findings demonstrated a gray-pink, soft tumor nodule with a visually indistinct tumor border and yellowish cyst wall. The patient was immediately seizure free, and the mental disorders showed improvement after surgery. MRI at the 6-month postoperative follow-up demonstrated no evidence of tumor recurrence despite receiving no further therapy. Microscopically, the neoplasm was predominantly composed of packed oval or round cells with small nuclei (Fig. 2a–b). Neither mitosis nor significant nuclear atypia were identified in the predominant tumor cells. The tumor border included neurons with prominent nuclei and nucleoli and ample cytoplasm which were relatively well ordered without particular dysmorphism, suggesting entrapped pre-existing elements. The tumor lesion included increased capillaries with nuclear atypia on the endothelial cells, and the surrounding tumor cells demonstrated capillary-like tubule formation (Fig. 2c–d). These findings suggested the possibility of tumor cells converting into tumoral endothelial cells. Scattered calcifications were noted predominantly in the peritumoral region. Necrotic foci were absent. Tumor cells did not extend into the subarachnoid space. Silver staining confirmed the absence of reticulin fibers among the individual tumor cells (Fig. 2e). The tumor was devoid of Rosenthal fibers, eosinophilic granular bodies, and a biphasic compact/microcystic pattern as well as cellular polymorphism and xanthomatous changes, which are the characteristics of pilocytic astrocytoma and pleomorphic xanthoastrocytoma (PXA), respectively. Immunohistochemistry revealed intense immunopositivity for S100, Olig2, MGMT, vimentin, CD34 and nestin on the tumor cells (Fig. 2f–i). The tumor cells showed focally positive for p53, but showed negative for epithelial membrane antigen, asmooth muscle actin, neurofilament, neuronal nuclear antigen, glial fibrillary acidic protein (GFAP), and mutant IDH1 staining (Fig. 2j). Immunostaining with nestin confirmed that the tumor cells infrequently contain cytoplasmic process. The MIB-1 labeling index was 1.1 %. The relatively distinct border between the tumor region and & Masaya Nagaishi nagaishi-nsu@umin.ac.jp

Epithelioid glioblastomas are one of the rarest histological variants of glioblastomas, which are not formally recognized by the World Health Organization (WHO) classification. Epithelioid glioblastomas usually occur as primary lesions, but there have been several reports of secondary epithelioid glioblastomas or epithelioid glioblastomas with pre- or co-existing lesions to date. The serine/threonine-protein kinase B-Raf (BRAF) V600E mutation has been found at a high frequency of 54% in epithelioid glioblastomas. We present a case of a 26-year-old female patient with an epithelioid glioblastoma with the BRAF V600E mutation in her right frontal lobe. In the present case, a low-grade diffuse astrocytoma component had colocalized with the epithelioid glioblastoma. The component presented prominent calcification on neuroimages as well as by histology, and low-grade diffuse astrocytoma was considered to be a precursor lesion of an epithelioid glioblastoma. However, the BRAF V600E mutation was detected only in epithelioid glioblastoma but not in low-grade diffuse astrocytoma. To the best of our knowledge, this is the first report demonstrating a discrepancy in the BRAF V600E mutation states between epithelioid glioblastoma and colocalized low-grade astrocytoma.

Oligodendroglial tumors with neuronal differentiation cases have been reported in recent studies. Oligodendrocyte precursor cells (OPCs) give rise to both oligodendrocytes and neurons; however, little is known about the association between OPCs and oligodendroglial tumors with neuronal differentiation. Previously, we observed the coexpression of cyclin D1, one of the OPC markers, and alpha-internexin (INA) in oligodendroglial tumor cells. INA is a neuronal marker, and has been indicated as an immunohistochemical surrogate of chromosome 1p/19q co-deletion in oligodendroglial tumors. In this study, we investigated the expression status in 83 gliomas immunohistochemically, and found that cyclin D1-positive cells were commonly detected in gliomas. There was no correlation between the cyclin D1 and Ki-67 labeling indices, suggesting an unrecognized role of cyclin D1 other than a cell cycle regulator in gliomas. Cyclin D1/INA double-positive cells were consistently observed in oligodendroglial tumors regardless of histological grade. In 2 cases of oligodendroglioma with neuronal differentiation, the tumor cells of neuronal morphology showed higher expression of INA, suggesting INA expression may be associated with a bona fide neuronal phenotype. The prevalence of cyclin D1/INA double-positive cells is a distinct feature of oligodendroglial tumors. This new characteristic finding may have practical utility in glioma classification.

Multinodular and vacuolating neuronal tumors (MVNT) have been recently referred to as a distinctive neuronal tumor entity based on histopathological findings. They are characterized by multiple tumor nodules, vacuolar alteration and widespread immunolabeling for human neuronal protein HuC/HuD. Only 13 cases have been reported in the literature to date and little is known about the histopathology of these tumors. Herein, we report a case of MVNT with additional confirmation of immunohistochemical features. A 22-year-old woman presented with a continuous headache. MRI showed a subcortical white matter lesion with multiple satellite nodules in the frontal lobe appearing as T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. Histological examination of the resected lesion revealed well-defined multiple nodules composed of predominant vacuolating tumor cells. The tumor cells exhibited consistent immunolabeling for doublecortin, as well as HuC/HuD, both representative neuronal biomarkers associated with earlier stages of neuronal development. Immunopositivity for oligodendrocyte transcription factor 2 (Olig2) and S100 was also detected in tumor cells. Additionally, significant overexpression of alpha-internexin was observed in the background neuropil limited to tumor nodules. Neuronal nuclear antigen (NeuN), synaptophysin and neurofilament, markers for mature neurons, were either negative or weakly positive. The expression profile of neuronal biomarkers can be distinguished from that of classic neuronal tumors and is the immunohistochemical hallmark of MVNT. In summary, we identified the characteristic tumoral expression of HuC/HuD and doublecortin and the presence of abundant neuropil localized in MVNT tumor nodules, which exhibited widespread alpha-internexin expression. These results supported the presumption that MVNT is a distinct histopathological entity.

Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation.