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.     

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 Tumors of the Pleura: Advances Since the 2015 Classification

Substantial changes in the 2021 WHO Classification of Tumors of the Pleura and Pericardium since the 2015 WHO Classification include the following: (1) pleural and pericardial tumors have been combined in one chapter whereas in the 2015 WHO, pericardial tumors were classified with cardiac tumors; (2) well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumor given growing evidence that these tumors exhibit relatively indolent behavior; (3) localized and diffuse mesothelioma no longer include the term “malignant” as a prefix; (4) mesothelioma in situ has been added to the 2021 classification because these lesions can now be recognized by loss of BAP1 and/or MTAP by immunohistochemistry and/or CDKN2A homozygous deletion by fluorescence in situ hybridization; (5) the three main histologic subtypes (i.e., epithelioid, biphasic, and sarcomatoid) remain the same but architectural patterns and cytologic and stromal features are more formally incorporated into the 2021 classification on the basis of their prognostic significance; (6) nuclear grading for epithelioid diffuse mesothelioma is introduced, and it is recommended to record this and other histologically prognostic features in pathology reports; (7) BAP1, EZH2, and MTAP immunohistochemistry have been found to be useful in separating benign mesothelial proliferations from mesothelioma; (8) biphasic mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10%; and (9) the most frequently altered genes in diffuse pleural mesothelioma include BAP1, CDKN2A, NF2, TP53, SETD2, and SETDB1.     

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 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic,Clinical and Radiologic Advances Since the 2004 Classification

The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes in this edition involve (1) use of immunohistochemistry throughout the classification, (2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (6) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (7) grouping of neuroendocrine tumors together in one category, (8) adding NUT carcinoma, (9) changing the term sclerosing hemangioma to sclerosing pneumocytoma, (10) changing the name hamartoma to “pulmonary hamartoma,” (11) creating a group of PEComatous tumors that include (a) lymphangioleiomyomatosis, (b) PEComa, benign (with clear cell tumor as a variant) and (c) PEComa, malignant, (12) introducing the entity pulmonary myxoid sarcoma with an EWSR1–CREB1 translocation, (13) adding the entities myoepithelioma and myoepithelial carcinomas, which can show EWSR1 gene rearrangements, (14) recognition of usefulness of WWTR1–CAMTA1 fusions in diagnosis of epithelioid hemangioendotheliomas, (15) adding Erdheim–Chester disease to the lymphoproliferative tumor, and (16) a group of tumors of ectopic origin to include germ cell tumors, intrapulmonary thymoma, melanoma and meningioma.     

最新国际肺腺癌分类方法回顾性分析具有细支气管肺泡癌特征的肺腺癌209例

  目的   探讨最新国际肺腺癌分类中肺腺癌各组织学亚型与预后的相关性。  方法   收集天津医科大学附属肿瘤医院2000年1月至2005年12月间经手术切除、病理诊断为细支气管肺泡癌(bronchioloalveolar carcinoma, BAC)或伴有BAC成分的腺癌209例。按照肺癌新分类, 对所有病例组织学切片进行复习和分类, 同时进行临床资料的收集和随访。  结果   原诊断BAC的209例病例中原位腺癌(adenocarcinoma in situ, AIS)20例, 微小浸润性腺癌(minimally invasive adenocarcinoma, MIA)13例, 鳞屑样生长方式为主型腺癌(Lepidic predominant adenocarcinoma, LPA)82例, 乳头状和腺泡状为主型55例, 实性型和微乳头为主型39例。随访发现, 腺癌的组织学亚型与5年生存率有显著的相关性, AIS和MIA两组患者的5年生存率均为100%, 且均无淋巴结转移; LPA患者5年生存率为54.5%;腺泡型和乳头型腺癌的患者比AIS、MIA、LPA三组预后差, 而实性型和微乳头型的病例预后最差。  结论   肺腺癌中AIS和MIA有独特的临床病理特征及较好的预后。对具有细支气管肺泡癌特征的肺腺癌, 严格按照最新国际肺腺癌分类标准进行亚型分型, 对指导临床治疗及预测预后有重要意义。      

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。     

2015版犠犎犗肺肿瘤组织学分类解读

对第4版（2015年）WHO 肺肿瘤分类与第3版（2004年）肿瘤分类进行比较,并复习相关文献。2015版肿瘤分类作了大量的改动,对肺肿瘤的分类做了一些修改,新增了6个病种,即 NUT 中线癌、肌上皮肿瘤、伴有 EWSR1-CREB1基因易位的肺黏液样肉瘤、血管内大 B 细胞淋巴瘤、Erdheim-Chester 病和脑膜瘤非特异型;更新了肺癌的分子病理和免疫组织化学等内容,强调了肺癌相关基因的检测与靶向治疗。对一些肿瘤作了重新命名,如硬化性血管瘤命名为硬化性肺泡细胞瘤,使用贴壁型腺癌代替原先的细支气管肺泡癌。     

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.     

TGF-² Signaling Pathway in Lung Adenocarcinoma Invasion

The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-² signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-² type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.     

Defining Morphologic Features of Invasion in Pulmonary Nonmucinous Adenocarcinoma With Lepidic Growth: A Proposal by the International Association for the Study of Lung Cancer Pathology Committee

IntroductionSince the eight edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas.MethodsA Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and noninvasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size.ResultsThe mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%–22.3%) and 54% (range: 14.7%–155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces.ConclusionsCollapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement.     

let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis

It has been proposed that reduced let-7 expression causes RAS expression and correlates with poor survival of lung cancer cases, but little is known about correlations with clinicopathologic features. In this study, we examined 15 early bronchioloalveolar carcinomas (BACs), usually considered as adenocarcinomas in situ, as well as 26 well-differentiated and 25 less-differentiated invasive adenocarcinomas, to assess the association between tumor progression and let-7 expression levels. Additionally, we investigated 47 invasive lung adenocarcinomas for EGFR and KRAS mutations and correlations with let-7 levels. Relative to the corresponding normal lung tissue, reduced let-7 expression was observed in 13 of 15 BACs (87%) and totally in 52 of the 66 adenocarcinomas (79%), suggesting a link with early occurrence in carcinogenesis. On classification of adenocarcinomas into two groups according to let-7 expression, no prognostic or genetic differences were observed. Interestingly, some differences between histological subtypes were observed, such as lower let-7 expression levels in acinar adenocarcinomas and mucinous BACs.     

乳腺神经内分泌肿瘤诊治争议与进展

乳腺神经内分泌肿瘤是一组异质性肿瘤,既包括乳腺神经内分泌肿瘤,也包括伴有神经内分泌分化的乳腺浸润性癌。从20世纪60年代开始,学术界对此类肿瘤的定义、诊断标准等方面经历了反复的变化。由于对其缺乏严格的定义,此类肿瘤的名称较为混乱,诊断名词应用存在争议。世界卫生组织（WHO）第5版提出了新的乳腺神经内分泌肿瘤诊断标准。本文从乳腺神经内分泌肿瘤的命名沿革与定义、分类和病理形态学特点及免疫标志物、分子遗传学变化、临床特征、临床治疗和预后以及目前仍存在的问题等多个方面进行梳理。鉴于乳腺神经内分泌肿瘤仍有较多需要解决的问题,建议国内同仁制定乳腺神经内分泌肿瘤相关诊断术语的使用规范,在对临床上比较罕见的原发性乳腺神经内分泌肿瘤进行深入研究的同时,针对伴有神经内分泌分化的浸润性乳腺癌开展多中心、分层规范化研究。      

The cytologic basis for classification of lung tumors

Nuclear changes in cells of bronchial biopsies and surgical specimens were studied in relation to nuclear structures of cells at various mitotic phases. Cell structures comparable to early and late G1 and G2 phases were correlated with histologic types of lung tumors according to the 1981 WHO classification. The evolved cellular classification added another parameter for diagnosis of histologic alterations and for interpretation of cellular changes in cytologic specimens. Benign histological alterations contained cells in either early or late G1 phase. Well-differentiated adenocarcinomas, bronchiolo-alveolar cell carcinomas, and carcinoid tumors had cells with structure of the late G1 phase. These were distinguished from benign cells with similar structures by their increased nuclear size, their increased amount of nuclear chromatin, hyperchromasia, and increased nuclear cytoplasmic ratio. Well-differentiated acinar adenocarcinomas, papillary adenocarcinomas, clear cell carcinomas, and large cell carcinomas had cribriform nuclear structures with prominent nucleoli related to early G2 phase. Squamous cell carcinomas, poorly differentiated adenocarcinomas, giant cell carcinomas, and solid carcinomas with mucus formation had usually prominent nucleoli with nuclear structures of the late G2 phase. Small cell carcinomas were the only malignant tumors of the lung that had cells with the malignant cribriform nuclear structure of the early G2 phase without a nucleolus. Cellular markers of malignant neoplasms had also the nuclear structure of early G2 without a nucleolus but differed from small cell carcinoma by their differentiated state with presence of cilia. The cytologic diagnosis of 506 malignant tumors of 1031 cases examined resulted in a sensitivity of 86.6%. The correct diagnosis of 244 of 247 cases without tumor resulted in a diagnostic specificity of 98.8%.     

Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung

Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen κ statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (κ score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.     

Problems in the histological classification of bronchial carcinomas

Different histological classifications of pulmonary tumors, proposed and adopted over the last five decades, are briefly reviewed. Referring to the revised Histological Classification of Lung Tumors that was edited by an international committee of lung pathologists for WHO in 1977, different histologic types of bronchus carcinoma are presented in separate groups. Squamous carcinoma, small cell carcinoma, adenocarcinoma, and large cell carcinoma are differentiated in supra- and subgroups. Specific problems arising in the classification of mixed or combined tumors manifesting coexistence of different histologic growth types in the same tumor, are discussed in detail.