Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2025.105715
Jan Delabie, Ali Sakhdari
{"title":"Indolent clonal lymphoid disorders","authors":"Jan Delabie, Ali Sakhdari","doi":"10.1016/j.humpath.2025.105715","DOIUrl":"10.1016/j.humpath.2025.105715","url":null,"abstract":"<div><div>Indolent clonal lymphoid disorders are not recognized as lymphomas as they generally need no systemic treatment, and depending on the lesion, need only limited clinical follow-up. These lesions are usually incidentally diagnosed during the work up for other disease. The recognition of indolent clonal lymphoid disorders is important to avoid misdiagnosis as lymphoma and unnecessary treatment. Notwithstanding, some indolent disorders, especially B-cell disorders, may give important morbidity that is not related to disease burden but related to auto-immune disease which may need treatment. Further, some of these lesions may, at various rates, ultimately progress to lymphoma. As such, the indolent clonal lymphoid disorders also give an insight into the earliest stages of clonal lymphoid disease that may increase our understanding of lymphoma, although much needs yet to be elucidated. In this article both B- and T-cell indolent clonal lymphoid disorders are reviewed. Not included in this review are lymphoid lesions that may be mistaken for lymphoma, but are not clonal, such as indolent T-lymphoblastic proliferation or marginal zone hyperplasia with immunoglobulin light chain restriction. Further, an emphasis has been given to clonal lymphoid lesions and therefore indolent plasma cell lesions have not been included. Also excluded is indolent lymphoma that may not need treatment but nonetheless requires more regular follow up. One may rightfully argue that there may be a gray zone between what constitutes an indolent clonal lymphoid disorder and an indolent lymphoma. This discussion is reflected in the different terminology used for some entities between editions of the WHO classification and between the Fifth Edition of the WHO Classification and the International Consensus Classification (ICC). The former has been used as a selection basis for this review, but cross-reference has been made to the ICC nomenclature when that differs as well as to the earlier Revised Fourth Edition of the WHO Classification (WHO-r4). For this reason, indolent T-cell lymphoma of the gastrointestinal tract (ICC: indolent clonal T-cell lymphoproliferative disorder of the gastrointestinal tract) is not included in this review.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105715"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical use of circulating tumor DNA analysis in patients with lymphoma","authors":"Bettina Bisig , Karine Lefort , Sylvain Carras , Laurence de Leval","doi":"10.1016/j.humpath.2024.105679","DOIUrl":"10.1016/j.humpath.2024.105679","url":null,"abstract":"<div><div>The analysis of circulating tumor DNA (ctDNA) in liquid biopsy specimens has an established role for the detection of predictive molecular alterations and acquired resistance mutations in several tumors. The low-invasiveness of this approach allows for repeated sampling and dynamic monitoring of disease evolution. Originating from the entire body tumor bulk, plasma-derived ctDNA reflects intra- and interlesional genetic heterogeneity. In the management of lymphoma patients, ctDNA quantification at various timepoints of the patient’s clinical history is emerging as a complementary tool that may improve risk stratification, assessment of treatment response and early relapse detection during follow-up, most prominently in patients with diffuse large B-cell lymphoma or classic Hodgkin lymphoma. While liquid biopsies have not yet entered standard-of-care treatment protocols in these settings, several trials have provided evidence that at least a subset of lymphoma patients may benefit from the introduction of liquid biopsies into daily clinical care. In parallel, continuous technological developments have enabled highly sensitive ctDNA assessment methods, which span from locus-specific techniques identifying single hotspot mutations, to sequencing panels and genome-wide approaches that explore broader genetic and epigenetic alterations. Here, we provide an overview of current methods and ongoing technical developments for ctDNA evaluation. We also summarize the most important data from a selection of clinical studies that have explored the clinical use of ctDNA in several lymphoma entities.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105679"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105700
Lianqun Qiu, L. Jeffrey Medeiros, Shaoying Li
{"title":"High-grade B-cell lymphomas: Double hit and non-double hit","authors":"Lianqun Qiu, L. Jeffrey Medeiros, Shaoying Li","doi":"10.1016/j.humpath.2024.105700","DOIUrl":"10.1016/j.humpath.2024.105700","url":null,"abstract":"<div><div>The classification of high-grade B-cell lymphoma (HGBL) has continuously evolved over past decades. These neoplasms, as currently defined, represent about 2% of all non-Hodgkin lymphomas and patients with these neoplasms are often refractory or relapsed following standard therapy. The 5th edition of the World Health Organization classification of hematologic neoplasms (WHO-HAEM5) has refined the classification of HGBL and recognizes two types: (1) Diffuse large B-cell lymphoma (DLBCL)/HGBL with <em>MYC</em> and <em>BCL2</em> rearrangements, with or without <em>BCL6</em> rearrangements; and (2) HGBL, not otherwise specified (HGBL-NOS). WHO-HAEM5 excluded DLBCL/HGBL with concurrent <em>MYC</em> and <em>BCL6</em> rearrangements from this category and reclassified them into DLBCL or HGBL-NOS categories respectively based on morphology. The International Consensus Classification (ICC) takes a slightly different approach. In addition to recognizing the two WHO-HAEM5 categories, they recognize HGBL with concurrent <em>MYC</em> and <em>BCL6</em> rearrangements as a provisional entity. In this review, we provide an update of HGBL and its subgroups, focusing on their clinicopathologic features, diagnosis, molecular genetic features, and pathogenesis. Our diagnostic approach and caveats for differential diagnosis are also discussed with an emphasis on the differential diagnosis with B lymphoblastic leukemia/lymphoma.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105700"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105703
Hong Fang, Wei Wang, L. Jeffrey Medeiros
{"title":"Burkitt lymphoma","authors":"Hong Fang, Wei Wang, L. Jeffrey Medeiros","doi":"10.1016/j.humpath.2024.105703","DOIUrl":"10.1016/j.humpath.2024.105703","url":null,"abstract":"<div><div>Burkitt lymphoma is a mature aggressive B-cell neoplasm with distinctive clinical and morphologic features, a germinal center B-cell immunophenotype, a high proliferation index and <em>MYC</em> rearrangement with an immunoglobulin gene partner. Initially described in equatorial Africa by a surgeon, Denis Burkitt, African (endemic) Burkitt lymphoma was the first neoplasm shown to be associated with a virus, Epstein-Barr virus (EBV), and the first neoplasm shown to be associated with a chromosomal translocation, <em>IGH::MYC</em>. In this article, we provide a brief historical introduction of Burkitt lymphoma, followed by a review of all aspects of this neoplasm including pathogenesis, clinical presentation, morphology, immunophenotype, cytogenetics and molecular findings. We also provide recent updates of this entity, including advances in our understanding of molecular pathogenesis of Burkitt lymphoma and the recent proposal in the current World Health Organization classification that the traditional epidemiologic variants of Burkitt lymphoma are better replaced by presence or absence of EBV infection. We also discuss the differential diagnosis of Burkitt lymphoma and how this neoplasm can be distinguished from reactive conditions and other aggressive B-cell lymphomas/leukemias. Given its very rapid growth and the unique treatment approach employed to treat these patients, it is important to recognize Burkitt lymphoma to facilitate appropriate therapy.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105703"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105676
Jan Bosch-Schips , Xenia Parisi , Fina Climent , Francisco Vega
{"title":"Bridging clinicopathologic features and genetics in follicular lymphoma: Towards enhanced diagnostic accuracy and subtype differentiation","authors":"Jan Bosch-Schips , Xenia Parisi , Fina Climent , Francisco Vega","doi":"10.1016/j.humpath.2024.105676","DOIUrl":"10.1016/j.humpath.2024.105676","url":null,"abstract":"<div><div>Follicular lymphoma (FL) is a neoplasm that originates from germinal center B cells and typically forms at least a partial follicular pattern. Approximately 85% of FL cases harbor the t(14;18)(q32;q21)/<em>IGH::BCL2</em> which leads to the overexpression of BCL2. These cases are referred to as classic FL in the current World Health Organization classification [1]. These neoplasms often exhibit hallmark epigenetic deregulation due to recurrent mutations in genes such as <em>KMT2D</em>, <em>CREBBP</em>, and <em>EZH2,</em> with <em>KMT2D</em> and <em>CREBBP</em> considered founding events in FL lymphomagenesis. In contrast, about 15% of FL cases are negative for the t(14;18), which could present diagnostic challenges. These cases may lack the typical genetic markers and require careful pathological and molecular analysis for accurate diagnosis.</div><div>This review aims to provide an up-to-date pathology resource on FL, focusing on the pathological and molecular characteristics of these neoplasms. We will detail the diagnostic criteria for FL and emphasize the importance of genetic and mutational analyses in accurately characterizing and distinguishing FL subtypes. Furthermore, we will propose methodologies and best practices for the diagnostic work-up of FL to enhance diagnostic accuracy.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105676"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105698
Chi Young Ok, L. Jeffrey Medeiros
{"title":"Cyclin D1-negative mantle cell lymphoma","authors":"Chi Young Ok, L. Jeffrey Medeiros","doi":"10.1016/j.humpath.2024.105698","DOIUrl":"10.1016/j.humpath.2024.105698","url":null,"abstract":"<div><div>Cyclin D1-negative mantle cell lymphoma (MCL) is regarded as a B-cell neoplasm that has morphologic and immunophenotypic findings indistinguishable from typical MCL. These neoplasms lack cyclin D1 overexpression by immunohistochemistry and t(11;14)(q13;q32)/<em>IGH::CCND1</em>. Since cyclin D1-negative MCL was first recognized by gene expression profiling in 2003, there has been diagnostic confusion regarding this entity, mostly attributable to a lack of diagnostic tools to recognize these neoplasms in most clinical laboratories. Accumulated data show that most cyclin D1-negative MCL cases harbor <em>CCND2</em> or <em>CCND3</em> translocation with a variety of gene partners. In this review, the concept of cyclin D1-negative MCL is discussed in chronological order to further our understanding of this entity. We then discuss currently available diagnostic approaches and we conclude with future directions. We also suggest that the more specific terms <em>CCND2</em>-rearranged MCL or <em>CCND3</em>-rearranged MCL be used for neoplasms in which the rearranged gene is known, and that we reserve the term cyclin D1-negative MCL for neoplasms in which the rearranged gene in unknown.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105698"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105697
Ashley K. Volaric , Yuri Fedoriw
{"title":"Epstein-Barr virus-associated B-cell lymphoproliferative disorders and lymphomas: Diagnostic overlaps and defining features","authors":"Ashley K. Volaric , Yuri Fedoriw","doi":"10.1016/j.humpath.2024.105697","DOIUrl":"10.1016/j.humpath.2024.105697","url":null,"abstract":"<div><div>This review explores four Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders (LPD) and lymphomas with significant diagnostic overlap: EBV(+) mucocutaneous ulcer (EBVMCU), EBV(+) polymorphic LPD, EBV(+) classic Hodgkin lymphoma (CHL), and EBV(+) diffuse large B-cell lymphoma (DLBCL). Each entity is compared for both overlapping and defining features of clinical presentation, morphology, immunohistochemical profile and EBV expression pattern and latency. Our aims for this review are to provide useful guidance to the practicing pathologist in the diagnosis of these EBV-associated entities.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105697"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lymphomas in 3D and 4D spaces","authors":"Martin-Leo Hansmann , Sonja Scharf , Patrick Wurzel , Sylvia Hartmann","doi":"10.1016/j.humpath.2024.105699","DOIUrl":"10.1016/j.humpath.2024.105699","url":null,"abstract":"<div><div>The cellular compartments in the lymph node form dynamic networks, enabling coordinated innate and adaptive immunological responses. This compartmentalization of the lymph node into subcompartments, such as the T and B zones, has been proven to be beneficial. The study of lymph node microarchitecture has yielded new insights into a range of fields, including anatomy, pathology and biological processes. This review focuses on three-dimensional (3D) and four-dimensional (4D) investigations of human lymph nodes, with a particular emphasis on comparisons with data obtained from mice. It will discuss the findings of 3D/4D investigations of human lymph nodes. The investigation of the immune system in 3D space and time offers numerous advantages over the analysis of thin tissue sections. It provides data that is not visible in two-dimensional (2D) representations. A comparison of volumes, surfaces, cell speeds, cell contact numbers, contact duration times, morphologies and other variables can be made in the context of immune responses and lymphomas. The evaluation of data, the application of statistics and the use of machine learning have all been demonstrated to be valuable. In conditions of reactivity and neoplasia, T cells are the fastest-moving cells. In contrast, B cells show slower movement and higher turning angles in reactive lymphoid tissue and lymphomas. Even slower than B cells are reticulum cells, like follicular dendritic reticulum cells (FDC) of the B zones and macrophages. Fast T cells are especially found in Hodgkin lymphomas and mantle cell lymphomas. Contact times between T and B cells differ between different lymphoma types and may prove useful in defining lymphomas. 4D technologies, which evaluate living tissue slices, are suitable for use in testing checkpoint blockers (such as nivolumab) and other therapeutic drugs or cells. Following incubation with nivolumab, the duration of contacts between CD4-positive T cells and CD30-positive Hodgkin-Reed-Sternberg cells was documented. The preliminary data indicate that 3D and 4D experiments in hematopathology may facilitate new insights into diagnostics, biology, and clinical applications, including the development of new lymphoma classifications.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105699"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105708
Lianqun Qiu, Pei Lin
{"title":"Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia, a decade after the discovery of MYD88L265P","authors":"Lianqun Qiu, Pei Lin","doi":"10.1016/j.humpath.2024.105708","DOIUrl":"10.1016/j.humpath.2024.105708","url":null,"abstract":"<div><div>There has been remarkable progress over the past 80 years since Jan Waldenstrom first described patients with a hyperviscosity syndrome related to IgM paraprotein in 1944. The definition of Waldenstrom macroglobulinemia (WM) has evolved from a clinical syndrome to a distinct clinicopathologic entity with characteristic morphology, immunophenotype and molecular features. The landmark discovery of <em>MYD88</em> mutation among most WM cases in 2012 marked the dawning of an era of molecular genomic exploration that led to a paradigm shift in clinical practice. In the current World Health Organization (WHO) classification of hematologic neoplasms, WM is included in the category of lymphoplasmacytic lymphoma (LPL) of which WM represents over 90% of cases. LPL/WM is also better defined, resolving ambiguity in many cases that would have been classified as “low-grade B-cell lymphoma with plasmacytic differentiation” a decade before. Nevertheless, challenges still face pathologists because criteria for distinguishing LPL/WM from other types of low-grade B-cell lymphoma, particularly marginal zone lymphoma (MZL), remain imperfect. In this review, we highlight the current understanding of LPL and WM brought to light by new discoveries, which in turn are increasingly translated to improved diagnosis and personalized therapy. Key concepts in the diagnosis and their clinical implications are emphasized. Controversies and challenges are also discussed.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105708"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human pathologyPub Date : 2025-02-01DOI: 10.1016/j.humpath.2024.105706
Joo Y. Song , Zenggang Pan
{"title":"Aberrant expression in lymphoma, a diagnostic pitfall","authors":"Joo Y. Song , Zenggang Pan","doi":"10.1016/j.humpath.2024.105706","DOIUrl":"10.1016/j.humpath.2024.105706","url":null,"abstract":"<div><div>One of the major difficulties in practical hematopathology is to accurately assign cell lineage and thus ensure proper classification of lymphomas. The lineage-specific markers of lymphoma are detected by immunohistochemistry or flow cytometry immunophenotypic methods. However, aberrant gain or loss of these markers is occasionally encountered during daily practice, which often creates diagnostic challenges. In addition, lymphoma may aberrantly express non-hematopoietic markers, and vice versa. This review article provides an overview of aberrant gain of expression of lineage-associated antigens in mature lymphoid neoplasms, including recommendations to avoid diagnostic pitfalls and ultimately to reach accurate diagnoses.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"156 ","pages":"Article 105706"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}