Genetic alterations in gliosarcoma and giant cell glioblastoma

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. This article is protected by copyright. All rights reserved

An autopsy study of a familial oculopharyngeal muscular dystrophy (OPMD) with distal spread and neurogenic involvement

An 81-year-old man from a family with a history of oculopharyngeal muscular dystrophy (OPMD) involving 6 members over 4 generations is described. The patient first noted drooping of his eyelids at the age of 65. Dysphagia and dysarthria occurred soon thereafter. At age 78, impairment of gait developed and progressive wasting occurred in the limbs with an initial distal distribution. Electromyography of several limb muscles displayed a mixed myopathic and neurogenic pattern with giant potentials. Examination at autopsy revealed slight loss of neurons in the anterior horns of the spinal cord, with scanty ghost cells, neuronophagia, and central chromatolysis. By light microscopy the limb muscles showed moderate small-group atrophy with severe myopathy and target fibers. The viscerocranial muscles, including the ocular, vocal, and tongue muscles, demonstrated only myopathic change with the typical features of progressive muscular dystrophy. Advanced replacement by fibrous connective tissue and fat had occurred in both the viscerocranial and the lower limb muscles. The significance of neurogenic involvement in OPMD is discussed

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult

Intravascular Large B-Cell Lymphoma Presenting as Dementia and Hemolytic Anemia

Background: Intravascular lymphoma (IVL) is an uncommon disease characterized by atypical lymphoid cells growing inside the lumina of small vessels. The diversity of clinical presentation due to possible involvement of multiple organs often complicates its diagnosis. Case Report: Here, we report on a case of IVL with rapidly progressive dementia and Coombs-negative hemolytic anemia. Interestingly, the erythrocytes exhibited a decreased osmotic resistance. Bone marrow histopathology revealed increased erythropoiesis and, finally, a small monoclonal B lymphocyte population. Cerebral magnetic resonance imaging (MRI) demonstrated few micro-bleedings. Computed tomography (CT) showed bilateral ground-glass opacity of the lungs. Within a few days, the patient developed respiratory failure and died. On post-mortem examination, intravascular large B-cell lymphoma with almost complete infiltration of the brain and lungs was diagnosed. Conclusion: IVL should be considered early in situations of unexplained neuropsychiatric disease along with markedly elevated levels of lactic dehydrogenase, anemia, and hemolysis

65th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts, September 1–3, 2021

Dear participants, dear colleagues, It is our great pleasure to welcome you to the 65th Annual Meeting of the German Society of Neuropathology and Neuroanatomy - the brain and nerve microenvironment in health and disease - which will be held as a virtual meeting from September 1–3, 2021. The meeting will bring together basic and clinical researchers, physicians as well as junior scientists and PhD students from different disciplines of basic and clinical neuroscience. We will have outstanding lectures by and with some of the most renowned international experts in the field of neuro-oncology, neuroinflammation, neurodegeneration and muscle and nerve diseases and look forward to exciting scientific discussions. There will also be a special and timely section on the effects of COVID-19 on the central and peripheral nervous system. The three days will offer exciting insights into different areas of basic and clinical neuroscience. We have also encouraged early career scientists to present their scientific findings in short talks and poster presentations. We are therefore particularly thankful that the abstracts of the meeting, which in their sum provide the best overview of the high scientific standing of the field, will be published in Free Neuropathology. Finally, we would like to thank you all for your active contribution to this conference in these difficult times. We also thank all supporters for their financial help. We wish you a stimulating and exciting conference. Yours sincerely, Prof. Dr. med. Till Acker Conference Chair (Justus Liebig University Giessen Dr. med. Anne Schänzer Dr. med. Hildegard Dohme

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients