Embryonal and non‐meningothelial mesenchymal tumors of the central nervous system – Advances in diagnosis and prognostication

The 5th edition of the WHO Classification of Tumours of the Central Nervous System introduces new entities, and provides updated guidance regarding the diagnostic criteria for tumors of the central nervous system (CNS). CNS embryonal tumors and CNS non‐meningothelial mesenchymal tumors can be challenging for practicing pathologists, as the histologic features are not always specific to a particular entity, and integration of microscopic and molecular findings is necessary. This review on CNS embryonal and non‐meningothelial mesenchymal tumors is meant to provide an update with a focus on WHO changes and additions and on recent discoveries with diagnostic, prognostic, and therapeutic implications.     

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.     

v—sis和c—myc mRNA表达在脑膜瘤中的作用

本实验用原位杂交结合图像分析的方法对２８例脑膜瘤中ｖ－ｓｉｓ和ｃ－ｍｙｃ的ｍＲＮＡ表达状况进行了定位，定位，定量研究。结果表明：ｖ－ｓｉｓ和ｃ－ｍｙｃ ｍＲＮＡ在脑膜瘤中的高表达率分别为２８．６％和４６．４％，说明它们的表达增高在脑膜瘤中都有一定作用。相关分析发现，两种瘤基因的ｍＲＮＡ表达只在纤维细胞型脑膜瘤中呈正相关，说明ｖ－ｓｉｓ和ｃ－ｍｙｃ协同表达在ＦＭ中具有特异性作用，也说明各组织分型的脑     

Pathology and genetics of phaeochromocytoma and paraganglioma

Phaeochromocytoma and paraganglioma (PHEO/PGL) are rare tumours with an estimated annual incidence of 3 per million. Advances in molecular understanding have led to the recognition that at least 30–40% arise in the setting of hereditary disease. Germline mutations in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD and SDHAF2 are the most prevalent of the more than 19 hereditary genetic abnormalities which have been reported. It is therefore recommended that, depending on local resources and availability, at least some degree of genetic testing should be offered to all PHEO/PGL patients, including those with clinically sporadic disease. It is now accepted that that all PHEO/PGL have some metastatic potential; therefore, concepts of benign and malignant PHEO/PGL have no meaning and have been replaced by a risk stratification approach. Although there is broad acceptance that certain features, including high proliferative activity, invasive growth, increased cellularity, large tumour nests and comedonecrosis, are associated with an increased risk of metastasis, it remains difficult to predict the clinical behaviour of individual tumours and no single risk stratification scheme is endorsed or in widespread use. In this review, we provide an update on advances in the pathology and genetics of PHEO/PGL with an emphasis on the changes introduced in the WHO 2017 classification of endocrine neoplasia relevant to practising surgical pathologists.     

Evaluation of NF2 gene deletion in sporadic schwannomas, meningiomas, and ependymomas by chromogenic in situ hybridization

Fluorescence in situ hybridization, loss of heterozygosity testing, and comparative genomic hybridization have been used to detect NF2 gene alterations in both sporadic and neurofibromatosis type 2 (NF2)-associated central nervous system tumors. In this study, we performed chromogenic in situ hybridization (CISH) and immunohistochemistry to evaluate for NF2 gene deletion in a group of sporadic meningiomas, schwannomas, and ependymomas. Twenty-two sporadic tumors, including 9 ependymomas, 10 meningiomas, and 3 schwannomas, were studied. CISH and immunohistochemistry were performed using the NF2 gene deletion probe and NF2 polyclonal antibody. Deletion of the NF2 gene was identified in 11 (50%) tumors, including 60% (6/10) of meningiomas, 33% (3/9) of ependymomas, and 67% (2/3) of schwannomas. The remaining 11 (50%) cases were diploid. Overall, immunoexpression of NF2 protein was observed in 50% (11/22) tumors, and concordance between CISH and immunohistochemistry was observed in 73% of cases. Our results support previous observations that schwannomas and meningiomas, and to a lesser degree, ependymomas, express a high incidence of NF2 gene deletion, which supports the hypothesis that NF2 gene plays an important role in their tumorigenesis. In addition, we have validated CISH as an efficient, economic, and reliable method for routinely assessing NF2 gene deletion in these tumors.     

Pathology and molecular genetics of oligodendroglial tumors

Oligodendroglial gliomas are second only to astrocytic gliomas in frequency. The lack of stringent diagnostic criteria cause high interobserver variation in regard to classification and grading of these tumors. Previous studies have described oligodendrogliomas with features that overlap with those of neurocytic tumors, thus further complicating diagnostic decisions. The increasing need for standardized diagnostic criteria in this subset of gliomas is emphasized by the benefit of adjuvant therapies in patients with anaplastic oligodendrogliomas. Characteristic chromosomal aberrations have been successfully determined for oligodendroglial tumors in recent years. In contrast to astrocytomas, however, no genes in the affected regions have been clearly linked to their pathogenesis. However, the molecular findings promise to be helpful for diagnostic and therapeutic decisions. This review compiles clinical, pathological, and molecular genetic findings on WHO grades II and III oligodendrogliomas and oligoastrocytomas.     

Pathology and molecular genetics of astrocytic gliomas

Astrocytic gliomas are the most common primary brain tumours. Here we summarize the characteristic neuropathological features of the different types of astrocytic neoplasms according to the World Health Organization classification of tumours of the nervous system. In addition, we report on the present state of the art concerning the molecular genetics of these tumours. Over the past 20 years a number of recurrent chromosomal, genetic and epigenetic alterations have been found to be associated with the different histological types and malignancy grades of astrocytic tumours. However, we are still far from understanding the complex mechanisms that underly tumour initiation and progression in the individual case. Furthermore, the clinical significance of molecular parameters for the diagnostic and prognostic assessment of astrocytic gliomas is still limited. Therefore further investigation of the molecular mechanisms underlying oncogenesis and progression of these most common brain tumours is necessary to improve their diagnostic assessment and to devise novel, individually tailored treatment strategies.     

复杂性疾病遗传学研究进展

近十年,随着人类基因组计划的建立及不断完善、遗传学队列研究和基因分型技术的日趋成熟,复杂性疾病遗传背景的研究获得了突飞猛进的发展.迄今已发现数百个与复杂性疾病存在可靠关联的遗传变异,这为我们认识复杂性疾病发病机制提供了重要线索.该文将重点回顾近十年复杂性疾病遗传学研究的进展,主要包括:人类对基因组序列和结构认识的进步,复杂性疾病研究策略、队列的进步,基因分型技术的进展,最后简要概括这些进步对于复杂性疾病遗传学研究的新贡献.     

额颞叶痴呆的临床表型与遗传学研究进展

额颞叶痴呆是以人格改变,言语功能损害为主要特征,伴或不伴有运动功能损害的神经系统变性疾病。随着遗传学研究的不断深入,已发现20余种与额颞叶痴呆相关联的基因突变相关。额颞叶痴呆具有高度的临床和遗传异质性,本文总结了额颞叶痴呆临床表型与致病基因的关联性,旨在为疾病的诊断提供一定的线索。     

Medical genetics education for pediatrics residents: A brief report

PurposeGenetic testing is ubiquitous in the field of medicine and is often ordered or requested by primary care providers, nongenetics subspecialists, and patients themselves. Other studies have shown that providers are often not comfortable ordering genetic testing. There have been initiatives to teach these concepts via continuing medical education; however, there is not a standardized training program for teaching resident physicians about genetic testing.MethodsDuring September to October 2020, we recruited all the pediatrics residents at our institution via email (N = 102). Residents were invited to complete a Qualtrics electronic survey that addressed self-perceived level of knowledge about core concepts of genetic testing, as well as self-perceived confidence discussing these concepts with families.ResultsResponse rate was 46 to 102 (45%). Proportions of respondents reporting they felt insufficiently knowledgeable ranged from 28% (basic concepts of genetics) to 80% (Genetic Information Nondiscrimination Act). Most pediatrics residents agreed that a curriculum teaching basics of genetic testing would be helpful to them. Desired curricular topics included indications and limitations of genetic testing, testing procedures, and counseling families.ConclusionDespite its expanding importance across medicine, genetics education is lacking in pediatrics residency programs and residents would benefit from a curriculum teaching basic concepts of genetic testing.     

注意缺陷多动障碍(ADHD)患儿的遗传学研究进展

注意缺陷多动障碍（ADHD）是儿童期常见的一种行为障碍,因其对学习、生活有明显的影响,而且有些症状可持续到成年期,所以引起了人们广泛的关注。近年来,关于ADHD的遗传学研究成为一个热点,学者们做了大量的工作,获得了比较丰富的研究结果,一些关于ADHD的遗传理论在此基础上建立起来,增加了人们对该行为障碍本质的认识。本文拟对近年来ADHD遗传学领域的研究结果作一概述。     

不孕不育与遗传学相关因素的研究进展

不孕不育主要由遗传缺陷、解剖异常、内分泌紊乱、免疫因素、感染、全身性疾病及环境因素等各种原因引起。近年来,随着染色体显带技术的推广和应用,人们越来越多的发现,遗传因素对于了解不孕不育的原因及指导再次生育具有重要意义。本文就女性Turner综合征,男性克氏综合征,Y染色体的异态性,染色体倒位、易位、次缢痕变异等与不孕不育相关的异常染色体研究进展进行综述。     

Pathology, genetics and cytogenetics of Wilms' tumour

Wilms' tumour (WT) is an embryonal cancer of childhood and is thought to be derived from embryonic kidney precursor cells. The Knudson two hit model was initially thought to occur in WT, but findings emerging from genetic and cytogenetic studies in the past two decades have implicated several genetic events. Recent techniques in genetic analysis have improved our ability to characterise changes in genes involved in WT which include WT1, CTNNB1, IGF2 and WTX. These genetic events have not only provided insight into the pathobiology of this malignancy, but the recognition of these candidate genes may offer potential targets for novel therapies. In this review, we will provide an overview of the pathological, genetic and cytogenetic characteristics of WT.     

Pathology and genetics of anaplastic large cell lymphoma

Anaplastic large cell lymphomas are a rare subtype of peripheral/mature T-cell lymphomas which are clinically, pathologically and genetically heterogeneous. Both ALK-positive (ALK+) and ALK-negative (ALK-) ALCL are composed of large lymphoid cells with abundant cytoplasm and pleomorphic features with horseshoe-shaped and reniform nuclei. ALK+ ALCL were considered as a definite entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissues. ALK-ALCL was included as a provisional entity in the WHO 2008 edition and in the most recent 2017 edition, it is now considered a distinct entity that includes cytogenetic subsets that appear to have prognostic implications (e.g. 6p25 rearrangements at IRF4/DUSP22 locus). ALK+ ALCLs are distinct in epidemiology and pathogenetic origin and should be distinguished from ALK-ALCL, cutaneous ALCL and breast implant associated ALCL which have distinct clinical course and pathogenetic features. Breast implant-associated ALCL is now recognized as a new provisional entity distinct from other ALK-ALCL; notably that it is a noninvasive disease associated with excellent outcome. In this article, we will provide an overview of the salient themes relevant to the pathology and genetic mechanisms in ALCL.     

Imaging the genetics of executive function

Recent advances in neuroimaging technologies have allowed ever more detailed studies of the human brain. The combination of neuroimaging techniques with genetics may provide a more sensitive measure of the influence of genetic variants on cognitive function than behavioural measures alone. Here we present a review of functional magnetic resonance imaging (fMRI) studies of genetic links to executive functions, focusing on sustained attention, working memory and response inhibition. In addition to studies in the normal population, we also address findings from three clinical populations: schizophrenia, ADHD and autism spectrum disorders. While the findings in the populations studied do not always converge, they all point to the usefulness of neuroimaging techniques such as fMRI as potential endophenotypes for parsing the genetic aetiology of executive function.     

Expression of nestin, mesothelin and epithelial membrane antigen (EMA) in developing and adult human meninges and meningiomas

The spatial and temporal pattern of appearance of nestin, epithelial membrane antigen (EMA) and mesothelin proteins was immunohistochemically determined in the cells of normal developing and adult human meninges and meningiomas. Human meninges developed as two mesenchymal condensations in the head region. The simple squamous epithelium on the surface of leptomeninges developed during mesenchymal to epithelial transformation. Nestin appeared for the first time in week 7, EMA in week 8, while mesothelin appeared in week 22 of development. In the late fetal period and after birth, nestin expression decreased, whereas expression of EMA and mesothelin increased. EMA appeared in all surface epithelial cells and nodules, while mesothelin was found only in some of them. In adult meninges, all three proteins were predominantly localized in the surface epithelium and meningeal nodules. In meningothelial meningiomas (WHO grade I), EMA was detected in all tumor cells except in the endothelial cells, mesothelin characterized nests of tumor cells, while nestin was found predominantly in the walls of blood vessels. The distribution pattern of those proteins in normal meningeal and tumor cells indicates that nestin might characterize immature cells, while EMA and mesothelin appeared in maturing epithelial cells. Neoplastic transformation of these specific cell lineages contributes to the cell population in meningiomas.