The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.     

Molecular pathology of tumors of the central nervous system

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined ‘histo-molecular’ approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.     

WHO胸部肿瘤分类（第5版）中胸膜、心包及胸腺肿瘤部分解读

国际癌症研究机构（International Agency for Research on Cancer,IARC）于2021年5月出版了《WHO胸部肿瘤分类（第5版）》。与2015年出版的《WHO胸部肿瘤分类（第4版）》相比,《WHO胸部肿瘤分类（第5版）》变更了主要章节的框架,新增和调整部分疾病的命名和分类,并充实了流行病学、病因学、组织病理学和分子遗传学等相关内容。现就《WHO胸部肿瘤分类（第5版）》中胸膜、心包及胸腺肿瘤分类变化较大的内容予以简要介绍。     

WHO胸部肿瘤分类（第5版）中肺肿瘤部分解读

国际癌症研究机构（International Agency for Research on Cancer，IARC）于2021年5月出版了《WHO胸部肿瘤分类（第5版）》。与2015年出版的《WHO胸部肿瘤分类（第4版）》相比，《WHO胸部肿瘤分类（第5版）》变更了主要章节的框架，新增和调整了部分疾病的命名和分类，并充实了流行病学、病因学、组织病理学和分子遗传学等相关内容。现就《WHO胸部肿瘤分类（第5版）》中肺肿瘤分类变化较大的内容予以简要介绍。     

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial,Germ Cell,and Mesenchymal Tumors?

This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1^high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.     

The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015

The 2021 WHO Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry, and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are (1) broader emphasis on genetic testing than in the 2015 WHO Classification; (2) a section entirely dedicated to the classification of small diagnostic samples; (3) continued recommendation to document percentages of histologic patterns in invasive nonmucinous adenocarcinomas, with utilization of these features to apply a formal grading system, and using only invasive size for T-factor size determination in part lepidic nonmucinous lung adenocarcinomas as recommended by the eighth edition TNM classification; (4) recognition of spread through airspaces as a histologic feature with prognostic significance; (5) moving lymphoepithelial carcinoma to squamous cell carcinomas; (6) update on evolving concepts in lung neuroendocrine neoplasm classification; (7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor as a new entity within the adenoma subgroup; (8) recognition of thoracic SMARCA4-deficient undifferentiated tumor; and (9) inclusion of essential and desirable diagnostic criteria for each tumor.     

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.     

阑尾及结直肠肿瘤2019年第5版WHO分类变更解读

2019年第5版(以下简称"第5版")世界卫生组织(WHO)消化系统肿瘤新分类在2010年第4版(以下简称"第4版")的基础上对阑尾及结直肠肿瘤的相关内容做了较大的改动，增加了引言、锯齿状病变和息肉、黏液性肿瘤等内容，将不再推荐使用无蒂锯齿状息肉或腺瘤的诊断名称，改称为无蒂锯齿状病变，增加了未分类锯齿状腺瘤。第5版把混合性腺神经内分泌癌改称为混合性神经内分泌-非神经内分泌肿瘤，并指出两者具有克隆相关性，杯状细胞类癌不再被认为是神经内分泌肿瘤的一个亚型，改称为杯状细胞腺癌。第5版进一步细化结直肠腺癌的内容，把血管浸润分为肠壁内血管浸润和肠壁外血管浸润(超出黏膜肌)，后者发生率高于前者，而且预后更差。第5版认为肿瘤出芽及差分化癌细胞团是上皮间质转化的征兆，并且应用RNA测序或基于基因芯片技术，以肿瘤基因谱网络和转录组学分析的数据为基础，提出了共识分子分型。同时，第5版也更新了阑尾及结直肠肿瘤的TNM分期。为了帮助医务人员尽快熟悉第5版变更的内容，本文就更新后第4版与第5版的异同进行总结。      

弥漫性较低级别胶质瘤的整合性分子病理分型研究进展*

弥漫性较低级别胶质瘤包含WHOⅡ级和Ⅲ级的星形细胞瘤、少突胶质细胞瘤和少突星形细胞瘤,其临床表现具有高度可变性,目前的组织病理学无法准确地预测其预后。近年来,胶质瘤分子病理取得了重大进展,已经发现一系列与胶质瘤临床特征和预后密切相关的分子标志物如异柠檬酸脱氢酶（isocitrate dehydrogenase ,IDH ）突变、染色体1p/ 19q 共缺失、ATRX 基因突变、TERT启动子突变、MGMT 启动子甲基化等。在此基础上,结合这些分子标志物对弥漫性较低级别胶质瘤进行整合性分子病理分型的研究相继开展,且这些研究的结果一致表明,整合性分子病理分型能够更好地预测弥漫性较低级别胶质瘤的预后和指导治疗。本研究对弥漫性较低级别胶质瘤的整合性分子病理分型研究进展进行综述。      

Pathology of low- and intermediate-grade gliomas

Under the current World Health Organization (WHO) classification, gliomas can be divided into diffuse variants such as astrocytoma, oligodendroglioma, and mixed oligo-astrocytoma versus more discrete subtypes such as pilocytic astrocytoma and other less common entities. These tumors have been assigned histologic grades ranging from I to IV to reflect expected biological behavior. The ever-growing body of literature on genetic alterations of glial neoplasms promises to augment therapeutic and prognostic information in the future. An important example is the 1p and 19q deletions in oligodendrogliomas that recently have been associated with chemosensitivity and prolonged patient survival. This article reviews the pathology of low- and intermediate-grade gliomas, highlighting practical diagnostic and prognostic issues.     

脑胶质瘤的放射治疗临床研究进展

在全世界,每年约有176000例新发中枢神经系统肿瘤患者,而每年约有128000名患者死于这种疾病。脑胶质瘤约占所有中枢神经系统肿瘤中的42%,其中超过3/4的患者为恶性胶质瘤。放疗能提高大多数脑胶质瘤患者的生存期和生存质量。随着近年来放疗技术的进一步发展,脑胶质瘤术后放疗发生了很大的变化。本文将以WHO分级标准为线索,分别介绍各种脑胶质瘤放射治疗的临床研究进展。     

SEOM clinical guidelines for anaplastic gliomas (2017)

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.     

The Integrated Histopathologic and Molecular Approach to Adult-type Diffuse Astrocytomas: Status of the Art,Based on the 2021 WHO Classification of Central Nervous System Tumors

The 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) improved our understanding of the brain neoplasm biology. In more details, differences between diffuse gliomas that primarily occur in adults and those that primarily occur in children have been identified by the terms “adult-type” and “pediatric-type” diffuse gliomas. More importantly, both diagnostic and grading criteria for adult-type diffuse astrocytomas have been modified, by adopting novel molecular markers: diffuse astrocytomas, IDH-mutant have been grouped into a single entity and graded as CNS WHO grades 2, 3, or 4, with the assignment of Grade 4 in the presence of CDKN2A/B homozygous deletion, regardless of the histology [1]. Additionally, at least one of the following genetic alterations has been considered as sufficient to confer to astrocytomas, IDH wild type, a CNS WHO grade 4: i) TERT promoter mutation, ii) EGFR gene amplification, iii) combined gain of whole chromosome 7 and loss of whole chromosome 10 [+7/−10]. However, histology remains the solid basis to support these new complementary molecular data, and an integrated diagnosis is highly recommended.     

2016年版WHO淋巴肿瘤分类概述

2016年WHO淋巴肿瘤的修订版问世,内容较2008年版有些变化.文章结合过去8年内的一些临床、病理、遗传学和分子生物学的进展,阐明了一些非常早期的淋巴增生性病变的诊断和临床处理,修饰了一些淋巴瘤的诊断标准,深化了遗传学/分子生物学在多种淋巴瘤诊治中的意义.新的分类中也加入了少数临时的淋巴瘤类型.     

The World Health Organization's histologic classification of gastrointestinal tumors. A commentary on the second edition

The World Health Organization's (WHO) histologic classification of gastrointestinal tumors has been revised. Although the general basis of classification and the overall outline remain similar to the first edition, advances in the last decade justified changes in classifying certain entities; among them were malignant lymphomas, endocrine tumors, and dysplasias. Several newly recognized entities have also been added.     

Gene expression profiling of gliomas strongly predicts survival

In current clinical practice, histology-based grading of diffuse infiltrative gliomas is the best predictor of patient survival time. Yet histology provides little insight into the underlying biology of gliomas and is limited in its ability to identify and guide new molecularly targeted therapies. We have performed large-scale gene expression analysis using the Affymetrix HG U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of all histologic types to assess whether a gene expression-based, histology-independent classifier is predictive of survival and to determine whether gene expression signatures provide insight into the biology of gliomas. We found that gene expression-based grouping of tumors is a more powerful survival predictor than histologic grade or age. The poor prognosis samples could be grouped into three different poor prognosis groups, each with distinct molecular signatures. We further describe a list of 44 genes whose expression patterns reliably classify gliomas into previously unrecognized biological and prognostic groups: these genes are outstanding candidates for use in histology-independent classification of high-grade gliomas. The ability of the large scale and 44 gene set expression signatures to group tumors into strong survival groups was validated with an additional external and independent data set from another institution composed of 50 additional gliomas. This demonstrates that large-scale gene expression analysis and subset analysis of gliomas reveals unrecognized heterogeneity of tumors and is efficient at selecting prognosis-related gene expression differences which are able to be applied across institutions.     

SEOM clinical guideline of diagnosis and management of low-grade glioma (2017)

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk–benefit ratio of adjuvant treatment must be weighed for each individual.     

EANO guideline on the diagnosis and management of meningiomas

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.     

The WHO Histological Classification of Tumors of the Gallbladder and Extrahepatic Bile Ducts. A commentary on the second edition.

The second edition of the WHO Histological Classification of Tumors of the Gallbladder and Extrahepatic Bile Ducts is more comprehensive and detailed than the previous one. Advances in our understanding of dysplasia, carcinoma in situ, various lines of differentiation among the carcinomas, and the recognition of a variety of tumor-like lesions have resulted in more than three times as many entities in the current classification as in the previous one. The new edition should facilitate pathologic, epidemiologic, and therapeutic comparisons.