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      The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

      review-article
      1 , , 2 , , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 1 , 30 , 1 , 31 , 32 , 33 , 34 , 35 , 1 , 19 , 36 , 37 , 35 , 38 , 39 , 40 , 41 , 1 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 42 , 49 , 31 , 1 , 50 , 51 , 35 , 52 ,
      Leukemia
      Nature Publishing Group UK
      Haematological cancer, Diagnosis

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          Abstract

          The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

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          Age-related clonal hematopoiesis associated with adverse outcomes.

          The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
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            Revised international prognostic scoring system for myelodysplastic syndromes.

            The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
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              Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.

              Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.
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                Author and article information

                Contributors
                jkhoury@unmc.edu
                eric.solary@gustaveroussy.fr
                andreas.hochhaus@med.uni-jena.de
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                22 June 2022
                22 June 2022
                2022
                : 36
                : 7
                : 1703-1719
                Affiliations
                [1 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Hematopathology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [2 ]GRID grid.460789.4, ISNI 0000 0004 4910 6535, Department of Hematology, Gustave Roussy Cancer Center, , Université Paris-Saclay, ; Villejuif, France
                [3 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Division of Hematology/Oncology, , The Hospital for Sick Children, ; Toronto, ON Canada
                [4 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, The Steve and Cindy Rasmussen Institute for Genomic Medicine, , Nationwide Children’s Hospital, ; Columbus, OH USA
                [5 ]GRID grid.414125.7, ISNI 0000 0001 0727 6809, Pathology Unit, Department of Laboratories, , Bambino Gesu Children’s Hospital, IRCCS, ; Rome, Italy
                [6 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Centre for Haematology, , Imperial College London, ; London, UK
                [7 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Moores Cancer Center, , University of California San Diego, ; La Jolla, CA USA
                [8 ]University of Milan, Fondazione Cà Granda, IRCCS, Ospedale Maggiore Policlinico, Milano, Italy
                [9 ]GRID grid.14848.31, ISNI 0000 0001 2292 3357, Service d’hématologie, oncologie et transplantation, Hôpital Maisonneuve-Rosemont, , Université de Montréal, ; Montréal, QC Canada
                [10 ]GRID grid.415499.4, ISNI 0000 0004 1771 451X, Department of Pathology, , Queen Elizabeth Hospital, ; Kowloon, Hong Kong
                [11 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Pathology, , The University of Texas Southwestern Medical Center, ; Dallas, TX USA
                [12 ]GRID grid.34477.33, ISNI 0000000122986657, Department of Laboratory Medicine and Pathology, , University of Washington, ; Seattle, WA USA
                [13 ]GRID grid.440782.d, ISNI 0000 0004 0507 018X, Department of Hematology-Oncology, , 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.411107.2, ISNI 0000 0004 1767 5442, Department of Pathology, , Hospital Infantil Universitario Niño Jesús, ; Madrid, Spain
                [16 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Liverpool Clinical Laboratories, , Liverpool University Hospitals Foundation Trust, ; Liverpool, UK
                [17 ]GRID grid.5491.9, ISNI 0000 0004 1936 9297, Faculty of Medicine, , University of Southampton, ; Southampton, UK
                [18 ]GRID grid.509540.d, ISNI 0000 0004 6880 3010, Amsterdam UMC, , Location Vrije Universiteit Amsterdam, Department of Pathology, ; Amsterdam, The Netherlands
                [19 ]GRID grid.416975.8, ISNI 0000 0001 2200 2638, Department of Pathology & Immunology, , Baylor College of Medicine, Texas Children’s Hospital, ; Houston, TX USA
                [20 ]GRID grid.510308.f, ISNI 0000 0004 1771 3656, Department of Pathology, , Aichi Medical University Hospital, ; Nagakute, Japan
                [21 ]GRID grid.413756.2, ISNI 0000 0000 9982 5352, Department of Pathology, , Ambroise Pare Hospital, AP-HP and Versailles SQY University, ; Boulogne, France
                [22 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Pathology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [23 ]GRID grid.1649.a, ISNI 000000009445082X, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg and Department of Clinical Chemistry, , Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [24 ]GRID grid.462098.1, ISNI 0000 0004 0643 431X, Laboratory of Hematology, Assistance Publique-Hôpitaux de Paris, , Cochin Hospital and Université Paris Cité, CNRS, INSERM, Cochin Institute, ; Paris, France
                [25 ]GRID grid.411327.2, ISNI 0000 0001 2176 9917, Department of Hematology, Oncology, and Clinical Immunology, , Heinrich-Heine-University, ; Düsseldorf, Germany
                [26 ]GRID grid.410871.b, ISNI 0000 0004 1769 5793, Department of Pathology, , Tata Memorial Hospital, ; Mumbai, India
                [27 ]GRID grid.420057.4, ISNI 0000 0004 7553 8497, MLL Munich Leukemia Laboratory, ; Munich, Germany
                [28 ]GRID grid.420545.2, ISNI 0000 0004 0489 3985, Department of Haematology, , Guys and St Thomas’ NHS Foundation Trust, ; London, UK
                [29 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Indiana University School of Medicine, ; Indianapolis, IN USA
                [30 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Lab Hematology, Dept LABGK, Radboud University Medical Center, ; Nijmegen, The Netherlands
                [31 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Leukemia, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [32 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Pediatric Hematology and Oncology, , Hannover Medical School, ; Hannover, Germany
                [33 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Departments of Pathology and Oncology, , Fudan University, ; Shanghai, China
                [34 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pathology and Laboratory Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [35 ]GRID grid.270240.3, ISNI 0000 0001 2180 1622, Section of Pathology, Clinical Research Division, , Fred Hutchinson Cancer Center, ; Seattle, WA USA
                [36 ]GRID grid.270240.3, ISNI 0000 0001 2180 1622, Pediatric Hematology and Oncology, Clinical Research Division, , Fred Hutchinson Cancer Research Center, ; Seattle, WA USA
                [37 ]GRID grid.239395.7, ISNI 0000 0000 9011 8547, Department of Pathology, , Beth Israel Deaconess Medical Center, ; Boston, MA USA
                [38 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Pathology, , Stanford University School of Medicine, ; Stanford, CA USA
                [39 ]GRID grid.249335.a, ISNI 0000 0001 2218 7820, Department of Pathology, , Fox Chase Cancer Center, ; Philadelphia, PA USA
                [40 ]Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
                [41 ]GRID grid.468198.a, ISNI 0000 0000 9891 5233, Malignant Hematology, , H. Lee Moffitt Cancer Center and Research Institute, ; Tampa, FL USA
                [42 ]GRID grid.410871.b, ISNI 0000 0004 1769 5793, Hematopathology Laboratory, , Tata Memorial Hospital, ; Mumbai, India
                [43 ]GRID grid.239573.9, ISNI 0000 0000 9025 8099, Pathology and Lab Medicine, , Cincinnati Children’s Hospital Medical Center, ; Cincinnati, OH USA
                [44 ]GRID grid.411339.d, ISNI 0000 0000 8517 9062, Department of Hematology and Cellular Therapy, , University Hospital Leipzig, ; Leipzig, Germany
                [45 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Paediatrics, , University of Oxford, ; Oxford, UK
                [46 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Oncology, , University of Oxford, ; Oxford, UK
                [47 ]GRID grid.415306.5, ISNI 0000 0000 9983 6924, Immunology Division, , Garvan Institute of Medical Research, ; Sydney, Australia
                [48 ]GRID grid.410712.1, ISNI 0000 0004 0473 882X, Institute of Human Genetics, , Ulm University and Ulm University Medical Center, ; Ulm, Germany
                [49 ]GRID grid.5288.7, ISNI 0000 0000 9758 5690, Cell, Developmental & Cancer Biology Department, Knight Cancer Institute, , Oregon Health & Science University, ; Portland, OR USA
                [50 ]GRID grid.239546.f, ISNI 0000 0001 2153 6013, Department of Pathology and Laboratory Medicine, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA
                [51 ]GRID grid.51462.34, ISNI 0000 0001 2171 9952, Department of Pathology and Laboratory Medicine, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [52 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Hematology/Oncology, , Universitätsklinikum Jena, ; Jena, Germany
                Author information
                http://orcid.org/0000-0003-2621-3584
                http://orcid.org/0000-0002-8629-1341
                http://orcid.org/0000-0002-3072-7388
                http://orcid.org/0000-0002-1710-1794
                http://orcid.org/0000-0002-5603-4598
                http://orcid.org/0000-0002-5375-3749
                http://orcid.org/0000-0001-5638-4371
                http://orcid.org/0000-0002-2861-0180
                http://orcid.org/0000-0001-6859-187X
                http://orcid.org/0000-0001-5481-2555
                http://orcid.org/0000-0001-8284-567X
                http://orcid.org/0000-0002-6073-4466
                http://orcid.org/0000-0003-0196-2837
                http://orcid.org/0000-0001-7110-3814
                http://orcid.org/0000-0001-7829-5249
                http://orcid.org/0000-0002-1908-3307
                http://orcid.org/0000-0003-4120-5873
                http://orcid.org/0000-0001-8980-3202
                http://orcid.org/0000-0003-3807-3638
                http://orcid.org/0000-0002-9816-1018
                http://orcid.org/0000-0002-4707-7916
                http://orcid.org/0000-0001-9234-2857
                http://orcid.org/0000-0003-1863-3239
                http://orcid.org/0000-0002-3938-8490
                http://orcid.org/0000-0002-9030-0415
                http://orcid.org/0000-0002-2133-0960
                http://orcid.org/0000-0002-6912-8569
                http://orcid.org/0000-0001-6821-4556
                http://orcid.org/0000-0001-8586-8500
                http://orcid.org/0000-0001-6799-2022
                http://orcid.org/0000-0003-0626-0834
                Article
                1613
                10.1038/s41375-022-01613-1
                9252913
                35732831
                6cffe754-bd38-4b6e-90b0-ce755d127764
                © 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
                : 1 May 2022
                : 20 May 2022
                Categories
                Review Article
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                © The Author(s), under exclusive licence to Springer Nature Limited 2022

                Oncology & Radiotherapy
                haematological cancer,diagnosis
                Oncology & Radiotherapy
                haematological cancer, diagnosis

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