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      The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

      review-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , , 21 , 22 , , 11 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 39 , 40 , 41 , 42 , 21 , 43 , 22 , 44 , 33 , 45 , 33 , 46 , 47 , 48 , 22 , 49 , 23 , 50 , 35 , 51 , , 52 , 53 , 54 , 55 , 48 , 3 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , , 22 , 63 , 64 , 33 , 65 , 66 , 36 , 67 , 53
      Leukemia
      Nature Publishing Group UK
      Diagnosis, Lymphoma

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          Abstract

          We herein present an overview of the upcoming 5 th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4 th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5 th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

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          Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.

          Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 gene expression profiles using a cDNA microarray. Tissue microarray (TMA) blocks were created from 152 cases of DLBCL, 142 of which had been successfully evaluated by cDNA microarray (75 GCB, 41 ABC, and 26 type 3). Sections were stained with antibodies to CD10, bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. Expression of bcl-6 (P <.001) or CD10 (P =.019) was associated with better overall survival (OS), whereas expression of MUM1 (P =.009) or cyclin D2 (P <.001) was associated with worse OS. Cases were subclassified using CD10, bcl-6, and MUM1 expression, and 64 cases (42%) were considered GCB and 88 cases (58%) non-GCB. The 5-year OS for the GCB group was 76% compared with only 34% for the non-GCB group (P <.001), which is similar to that reported using the cDNA microarray. Bcl-2 and cyclin D2 were adverse predictors in the non-GCB group. In multivariate analysis, a high International Prognostic Index score (3-5) and the non-GCB phenotype were independent adverse predictors (P <.0001). In summary, immunostains can be used to determine the GCB and non-GCB subtypes of DLBCL and predict survival similar to the cDNA microarray.
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            Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

            We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
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              Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.

              Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
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                Author and article information

                Contributors
                mqd20@cam.ac.uk
                JFERRY@mgh.harvard.edu
                German.Ott@rbk.de
                reiner.siebert@uni-ulm.de
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                22 June 2022
                22 June 2022
                : 1-29
                Affiliations
                [1 ]GRID grid.414125.7, ISNI 0000 0001 0727 6809, Pathology Unit, Department of Laboratories, , Bambino Gesu Children’s Hospital, IRCCS, ; Rome, Italy
                [2 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Pathology, , University of Miami, ; Miami, FL USA
                [3 ]GRID grid.8379.5, ISNI 0000 0001 1958 8658, Institute of Pathology, , Julius-Maximilians-Universität Würzburg, ; Würzburg, Germany
                [4 ]GRID grid.424926.f, ISNI 0000 0004 0417 0461, Department of Histopathology, , Royal Marsden Hospital, ; London, UK
                [5 ]GRID grid.8399.b, ISNI 0000 0004 0372 8259, Department of Pathology, , Federal University of Bahia (UFBA), ; Salvador, Brazil
                [6 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, University of Milan, Fondazione Cà Granda, IRCCS, , Ospedale Maggiore Policlinico, ; Milan, Italy
                [7 ]GRID grid.21729.3f, ISNI 0000000419368729, Department of Pathology and Cell Biology, , Columbia University Irving Medical Center, ; New York, NY USA
                [8 ]GRID grid.477921.e, ISNI 0000 0004 1801 7716, Division of Histopathology, , SL Raheja Hospital, ; Mumbai, India
                [9 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Pathology, , University of Michigan, ; Ann Arbor, MI USA
                [10 ]GRID grid.139534.9, ISNI 0000 0001 0372 5777, Centre for Haemato-Oncology, Barts Cancer institute, , QMUL and SIHMDS Barts Health NHS Trust, ; London, UK
                [11 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Pathology and Laboratory Medicine, , Weill Cornell Medicine, ; New York, NY USA
                [12 ]GRID grid.415499.4, ISNI 0000 0004 1771 451X, Department of Pathology, , Queen Elizabeth Hospital, ; Kowloon, Hong Kong
                [13 ]GRID grid.440782.d, ISNI 0000 0004 0507 018X, National University Cancer Institute, ; Singapore, Singapore
                [14 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Pathology, , The University of Alabama at Birmingham, ; Birmingham, AL USA
                [15 ]GRID grid.413876.f, ISNI 0000 0004 0572 9255, Department of Pathology, , Chi-Mei Medical Center, ; Tainan, Taiwan
                [16 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Liverpool Clinical Laboratories, , Liverpool University Hospitals Foundation Trust, ; Liverpool, UK
                [17 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Department of Pathology and Laboratory Medicine, , Indiana University, ; Indianapolis, IN USA
                [18 ]GRID grid.26009.3d, ISNI 0000 0004 1936 7961, Center for Genomic and Computational Biology and Department of Medicine, , Duke University, ; Durham, NC USA
                [19 ]GRID grid.509540.d, ISNI 0000 0004 6880 3010, Amsterdam UMC, location Vrije Universiteit Amsterdam, , Department of Pathology, ; Amsterdam, The Netherlands
                [20 ]GRID grid.5335.0, ISNI 0000000121885934, Division of Cellular and Molecular Pathology, , Department of Pathology, University of Cambridge, ; Cambridge, UK
                [21 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pathology and Laboratory Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [22 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Pathology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [23 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Pathology, , Stanford University School of Medicine, ; Stanford, CA USA
                [24 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department. of Dermatology, , Northwestern University Feinberg Medical School, ; Chicago, IL USA
                [25 ]GRID grid.410871.b, ISNI 0000 0004 1769 5793, Department of Pathology, , Tata Memorial Hospital, ; Mumbai, India
                [26 ]GRID grid.2515.3, ISNI 0000 0004 0378 8438, Department of Pathology, , Boston Children’s Hospital, ; Boston, MA USA
                [27 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, , Newcastle University, ; Newcastle-upon-Tyne, UK
                [28 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Dr. Senckenberg Institute of Pathology, , Goethe University Frankfurt, ; Frankfurt am Main, Germany
                [29 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Hematology/Oncology, , Universitätsklinikum Jena, ; Jena, Germany
                [30 ]GRID grid.10419.3d, ISNI 0000000089452978, Leiden University Medical Center, , Department of Pathology, ; Leiden, The Netherlands
                [31 ]Department of Pathology and Laboratory Medicine, Nagoya, Japan
                [32 ]GRID grid.412004.3, ISNI 0000 0004 0478 9977, Kempf und Pfaltz Histologische Diagnostik Zurich, and Department of Dermatology, , University Hospital Zurich, ; Zurich, Switzerland
                [33 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Hematopathology, Division of Pathology and Laboratory Medicine, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [34 ]GRID grid.27476.30, ISNI 0000 0001 0943 978X, Department of Virology, , Nagoya University Graduate School of Medicine, ; Nagoya, Japan
                [35 ]GRID grid.9764.c, ISNI 0000 0001 2153 9986, Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, , University of Kiel, ; Kiel, Germany
                [36 ]GRID grid.239546.f, ISNI 0000 0001 2153 6013, Department of Pathology and Laboratory Medicine, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA
                [37 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Division of Hematology, , Mayo Clinic, ; Rochester, MN USA
                [38 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Departments of Pathology & Genomic Medicine, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [39 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Department of Medical Biotechnology, , University of Siena, ; Siena, Italy
                [40 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Division of Nephrology and Hypertension, Division of Hematology, , Mayo Clinic, ; Rochester, MN USA
                [41 ]GRID grid.30760.32, ISNI 0000 0001 2111 8460, Department of Pathology, , Medical College of Wisconsin and Children’s Wisconsin, ; Milwaukee, WI USA
                [42 ]GRID grid.452404.3, ISNI 0000 0004 1808 0942, Department of Pathology, , Fudan University Shanghai Cancer Center, ; Shanghai, China
                [43 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, Department of Pathology, , West-China Hospital, Sichuan University, ; Chengdu, China
                [44 ]GRID grid.416975.8, ISNI 0000 0001 2200 2638, Department of Pathology & Immunology, , Baylor College of Medicine and Texas Children’s Hospital, ; Houston, TX USA
                [45 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, Department of Pathology, Charles University in Prague, , Faculty of Medicine in Plzen, ; Plzen, Czech Republic
                [46 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Dermatology, Venereology and Allergology, , University Medical Center Göttingen, ; Göttingen, Germany
                [47 ]GRID grid.484299.a, ISNI 0000 0004 9288 8771, Anatomic Pathology Department and Translational Hematopathology Lab, , Valdecilla/IDIVAL University Hospital, ; Santander, Spain
                [48 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Laboratory Medicine and Pathology, , Mayo Clinic, ; Rochester, MN USA
                [49 ]GRID grid.270240.3, ISNI 0000 0001 2180 1622, Section of Pathology, Clinical Research Division, , Fred Hutchinson Cancer Center, ; Seattle, WA USA
                [50 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Department of Pathology, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore
                [51 ]Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
                [52 ]GRID grid.42399.35, ISNI 0000 0004 0593 7118, Department of Pathology, , Bordeaux University Hospital, ; Bordeaux, France
                [53 ]GRID grid.51462.34, ISNI 0000 0001 2171 9952, Department of Pathology and Laboratory Medicine, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [54 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Division of Hematology, , Mayo Clinic, Rochester, Minnesota, ; Rochester, MN USA
                [55 ]GRID grid.415967.8, ISNI 0000 0000 9965 1030, HMDS, Leeds Cancer Centre, , Leeds Teaching Hospitals NHS Trust, ; Leeds, UK
                [56 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Pathology and Laboratory Medicine, , University of California Los Angeles, ; Los Angeles, CA USA
                [57 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, MD-PhD, DITEP, Gustave Roussy, ; Villejuif, France
                [58 ]GRID grid.411192.e, ISNI 0000 0004 1756 6158, Department of Pathology- Aga Khan University Hospital- Nairobi, ; Nairobi, Kenya
                [59 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, Section of Hematology/Oncology, , University of Chicago, ; Chicago, IL USA
                [60 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Oncology, , University of Oxford, ; Oxford, UK
                [61 ]GRID grid.415306.5, ISNI 0000 0000 9983 6924, Immunology Division, , Garvan Institute of Medical Research, ; Sydney, Australia
                [62 ]GRID grid.410712.1, ISNI 0000 0004 0473 882X, Institute of Human Genetics, , Ulm University and Ulm University Medical Center, ; Ulm, Germany
                [63 ]GRID grid.9909.9, ISNI 0000 0004 1936 8403, Division of Haematology and Immunology, Leeds Institute of Medical Research, , University of Leeds, ; Leeds, UK
                [64 ]GRID grid.413852.9, ISNI 0000 0001 2163 3825, Hospices Civils de Lyon/Department of Pathology/ Université Lyon 1/ Centre International de Recherche en Infectiologie (CIRI) INSERM U1111 -, ; CNRS UMR5308 Lyon, France
                [65 ]GRID grid.42399.35, ISNI 0000 0004 0593 7118, Department of Pathology, , Hopital Haut-Lévêque, CHU Bordeaux, ; Pessac, France
                [66 ]GRID grid.83440.3b, ISNI 0000000121901201, National Amyloidosis Centre, , University College London, ; London, UK
                [67 ]GRID grid.418443.e, ISNI 0000 0004 0598 4440, Department of Pathology, , Institut Paoli-Calmettes and Aix-Marseillreference University, ; Marseille, France
                Author information
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                http://orcid.org/0000-0003-0352-5526
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                http://orcid.org/0000-0001-5034-8150
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                http://orcid.org/0000-0001-9948-3193
                http://orcid.org/0000-0003-4094-1633
                http://orcid.org/0000-0002-9499-8638
                http://orcid.org/0000-0001-5068-6707
                http://orcid.org/0000-0003-3160-9591
                http://orcid.org/0000-0003-2578-8335
                http://orcid.org/0000-0002-2861-0180
                http://orcid.org/0000-0003-3971-525X
                http://orcid.org/0000-0002-1464-2069
                http://orcid.org/0000-0002-6173-6500
                http://orcid.org/0000-0003-4848-9768
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                http://orcid.org/0000-0002-1017-5045
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                Article
                1620
                10.1038/s41375-022-01620-2
                9214472
                35732829
                7f79cb5d-6fae-426d-88a5-408e330d09e0
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 May 2022
                : 17 May 2022
                : 26 May 2022
                Categories
                Review Article

                Oncology & Radiotherapy
                diagnosis,lymphoma
                Oncology & Radiotherapy
                diagnosis, lymphoma

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