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

Hematologic Neoplasms Histiocytosis Humans World Health Organization

Journal

Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895

Informations de publication

Date de publication:
07 2022
Historique:
received: 01 05 2022
accepted: 20 05 2022
pubmed: 23 6 2022
medline: 8 7 2022
entrez: 22 6 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41375-022-01613-1 PMID: 35732831 PMC: PMC9252913
pubmed: 35732831
doi: 10.1038/s41375-022-01613-1
pii: 10.1038/s41375-022-01613-1
pmc: PMC9252913
doi:

Types de publication

Journal Article Review Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1703-1719

Subventions

Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : K08 CA267058
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12009/14
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022. The Author(s).

Références

Uttley L, Indave BI, Hyde C, White V, Lokuhetty D, Cree I. Invited commentary-WHO Classification of Tumours: How should tumors be classified? Expert consensus, systematic reviews or both? Int J Cancer. 2020;146:3516–21.
pubmed: 32170735 pmcid: 7818407 doi: 10.1002/ijc.32975
Salto-Tellez M, Cree IA. Cancer taxonomy: pathology beyond pathology. Eur J Cancer. 2019;115:57–60.
pubmed: 31108243 doi: 10.1016/j.ejca.2019.03.026
Cree I. The WHO Classification of Haematolymphoid Tumours. Leukemia. 2022;36:in press (same issue).
Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Barreto de Oliveira Araujo I, Berti E, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36:in press (same issue).
Bruford EA, Antonescu CR, Carroll AJ, Chinnaiyan A, Cree IA, Cross NCP, et al. HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions. Leukemia. 2021;35:3040–3.
pubmed: 34615987 pmcid: 8550944 doi: 10.1038/s41375-021-01436-6
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.
pubmed: 25426837 pmcid: 4306669 doi: 10.1056/NEJMoa1408617
Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383:2628–38.
pubmed: 33108101 pmcid: 7847551 doi: 10.1056/NEJMoa2026834
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.
pubmed: 25931582 pmcid: 4624443 doi: 10.1182/blood-2015-03-631747
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Cytopenia levels for aiding establishment of the diagnosis of myelodysplastic syndromes. Blood. 2016;128:2096–7.
pubmed: 27535995 pmcid: 5341483 doi: 10.1182/blood-2016-07-728766
Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.
pubmed: 28273028 pmcid: 5901965 doi: 10.1056/NEJMoa1609324
Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015;29:1123–32.
pubmed: 25676422 doi: 10.1038/leu.2015.36
Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127:2742–50.
pubmed: 27006386 pmcid: 4915795 doi: 10.1182/blood-2016-01-690230
Soverini S, Bavaro L, De Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood. 2020;135:534–41. Erratum in Blood. 2022;139:1601.
Guglielmelli P, Pacilli A, Rotunno G, Rumi E, Rosti V, Delaini F, et al. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129:3227–36.
pubmed: 28351937 doi: 10.1182/blood-2017-01-761999
Rumi E, Boveri E, Bellini M, Pietra D, Ferretti VV, Sant’Antonio E, et al. Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria. Oncotarget. 2017;8:101735–44.
pubmed: 29254200 pmcid: 5731910 doi: 10.18632/oncotarget.21594
Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29:3179–84.
pubmed: 21747083 doi: 10.1200/JCO.2010.34.5298
Szuber N, Finke CM, Lasho TL, Elliott MA, Hanson CA, Pardanani A, et al. CSF3R-mutated chronic neutrophilic leukemia: long-term outcome in 19 consecutive patients and risk model for survival. Blood Cancer J. 2018;8:21.
pubmed: 29449543 pmcid: 5814430 doi: 10.1038/s41408-018-0058-7
Pardanani A, Lasho TL, Laborde RR, Elliott M, Hanson CA, Knudson RA, et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013;27:1870–3.
pubmed: 23604229 pmcid: 4100617 doi: 10.1038/leu.2013.122
Pardanani A, Lasho T, Wassie E, Finke C, Zblewski D, Hanson CA, et al. Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing. Leukemia. 2016;30:1924–6.
pubmed: 27125206 doi: 10.1038/leu.2016.73
Cross NCP, Hoade Y, Tapper WJ, Carreno-Tarragona G, Fanelli T, Jawhar M, et al. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia. 2019;33:415–25.
pubmed: 30573779 doi: 10.1038/s41375-018-0342-3
Wang SA, Hasserjian RP, Tam W, Tsai AG, Geyer JT, George TI, et al. Bone marrow morphology is a strong discriminator between chronic eosinophilic leukemia, not otherwise specified and reactive idiopathic hypereosinophilic syndrome. Haematologica. 2017;102:1352–60.
pubmed: 28495918 pmcid: 5541870 doi: 10.3324/haematol.2017.165340
Fang H, Ketterling RP, Hanson CA, Pardanani A, Kurtin PJ, Chen D, et al. A test utilization approach to the diagnostic workup of isolated eosinophilia in otherwise morphologically unremarkable bone marrow: a single institutional experience. Am J Clin Pathol. 2018;150:421–31.
pubmed: 30032299 doi: 10.1093/ajcp/aqy064
Valent P, Akin C, Gleixner KV, Sperr WR, Reiter A, Arock M, et al. Multidisciplinary challenges in mastocytosis and how to address with personalized medicine approaches. Int J Mol Sci. 2019;20:2976.
Reiter A, George TI, Gotlib J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis. Blood. 2020;135:1365–76.
pubmed: 32106312 doi: 10.1182/blood.2019000932
Valent P, Akin C, Hartmann K, Alvarez-Twose I, Brockow K, Hermine O, et al. Updated diagnostic criteria and classification of mast cell disorders: a consensus proposal. Hemasphere. 2021;5:e646.
pubmed: 34901755 pmcid: 8659997 doi: 10.1097/HS9.0000000000000646
Alvarez-Twose I, Jara-Acevedo M, Morgado JM, Garcia-Montero A, Sanchez-Munoz L, Teodosio C, et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol. 2016;137:168–78.
pubmed: 26100086 doi: 10.1016/j.jaci.2015.05.008
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.
pubmed: 22740453 pmcid: 4425443 doi: 10.1182/blood-2012-03-420489
Malcovati L, Stevenson K, Papaemmanuil E, Neuberg D, Bejar R, Boultwood J, et al. SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS. Blood. 2020;136:157–70.
pubmed: 32347921 pmcid: 7362582 doi: 10.1182/blood.2020004850
Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26:1549–56.
pubmed: 32747829 pmcid: 8381722 doi: 10.1038/s41591-020-1008-z
Haase D, Stevenson KE, Neuberg D, Maciejewski JP, Nazha A, Sekeres MA, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33:1747–58.
pubmed: 30635634 pmcid: 6609480 doi: 10.1038/s41375-018-0351-2
Grob T, Al Hinai ASA, Sanders MA, Kavelaars FG, Rijken M, Gradowska PL, et al. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2022;139:2347–54.
pubmed: 35108372 doi: 10.1182/blood.2021014472
Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.
pubmed: 24220272 doi: 10.1038/leu.2013.336
Tashakori M, Kadia TM, Loghavi S, Daver NG, Kanagal-Shamanna R, Pierce SR, et al. TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia. Blood. 2022, in press.
Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.
pubmed: 26132940 pmcid: 7478337 doi: 10.1056/NEJMoa1414799
Nazha A, Seastone D, Radivoyevitch T, Przychodzen B, Carraway HE, Patel BJ, et al. Genomic patterns associated with hypoplastic compared to hyperplastic myelodysplastic syndromes. Haematologica. 2015;100:e434–7.
pubmed: 26273060 pmcid: 4825290 doi: 10.3324/haematol.2015.130112
Fattizzo B, Ireland R, Dunlop A, Yallop D, Kassam S, Large J, et al. Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia. Leukemia. 2021;35:3223–31.
pubmed: 33664463 pmcid: 8550969 doi: 10.1038/s41375-021-01190-9
Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal. Blood. 2022;139:323–32.
pubmed: 34111285 pmcid: 8832464 doi: 10.1182/blood.2021011304
DiNardo CD, Garcia-Manero G, Kantarjian HM. Time to blur the blast boundaries. Cancer. 2022;128:1568–70.
pubmed: 35133004 doi: 10.1002/cncr.34119
Chen X, Fromm JR, Naresh KN. “Blasts” in myeloid neoplasms - how do we define blasts and how do we incorporate them into diagnostic schema moving forward? Leukemia. 2022;36:327–32.
pubmed: 35042955 doi: 10.1038/s41375-021-01498-6
Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2017;31:759–62.
pubmed: 27876779 doi: 10.1038/leu.2016.342
Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.
pubmed: 29146900 pmcid: 5691144 doi: 10.1038/s41467-017-01590-5
Baumann I, Führer M, Behrendt S, Campr V, Csomor J, Furlan I, et al. Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology. 2012;61:10–7.
pubmed: 22458667 doi: 10.1111/j.1365-2559.2011.04156.x
Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27:1806–17.
pubmed: 34621053 doi: 10.1038/s41591-021-01511-6
Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020;33:101197.
pubmed: 33038986 pmcid: 7388796 doi: 10.1016/j.beha.2020.101197
Montalban-Bravo G, Kanagal-Shamanna R, Guerra V, Ramos-Perez J, Hammond D, Shilpa P, et al. Clinical outcomes and influence of mutation clonal dominance in oligomonocytic and classical chronic myelomonocytic leukemia. Am J Hematol. 2021;96:E50–E53.
pubmed: 33156969
Calvo X, Garcia-Gisbert N, Parraga I, Gibert J, Florensa L, Andrade-Campos M, et al. Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features. Blood Adv. 2020;4:5285–96.
pubmed: 33108455 pmcid: 7594385 doi: 10.1182/bloodadvances.2020002206
Geyer JT, Tam W, Liu YC, Chen Z, Wang SA, Bueso-Ramos C, et al. Oligomonocytic chronic myelomonocytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational profile to classical chronic myelomonocytic leukemia. Mod Pathol. 2017;30:1213–22.
pubmed: 28548124 doi: 10.1038/modpathol.2017.45
Patnaik MM, Timm MM, Vallapureddy R, Lasho TL, Ketterling RP, Gangat N, et al. Flow cytometry based monocyte subset analysis accurately distinguishes chronic myelomonocytic leukemia from myeloproliferative neoplasms with associated monocytosis. Blood Cancer J. 2017;7:e584.
pubmed: 28731458 pmcid: 5549258 doi: 10.1038/bcj.2017.66
Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015;125:3618–26.
pubmed: 25852055 pmcid: 4497970 doi: 10.1182/blood-2015-01-620781
Cargo C, Cullen M, Taylor J, Short M, Glover P, van Hoppe S, et al. The use of targeted sequencing and flow cytometry to identify patients with a clinically significant monocytosis. Blood. 2019;133:1325–34.
pubmed: 30606702 doi: 10.1182/blood-2018-08-867333
Carr RM, Vorobyev D, Lasho T, Marks DL, Tolosa EJ, Vedder A, et al. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nat Commun. 2021;12:2901.
pubmed: 34006870 pmcid: 8131698 doi: 10.1038/s41467-021-23186-w
Xicoy B, Triguero A, Such E, Garcia O, Jimenez MJ, Arnan M, et al. The division of chronic myelomonocytic leukemia (CMML)-1 into CMML-0 and CMML-1 according to 2016 World Health Organization (WHO) classification has no impact in outcome in a large series of patients from the Spanish group of MDS. Leuk Res. 2018;70:34–6.
pubmed: 29775844 doi: 10.1016/j.leukres.2018.05.003
Loghavi S, Sui D, Wei P, Garcia-Manero G, Pierce S, Routbort MJ, et al. Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories. Blood Adv. 2018;2:1807–16.
pubmed: 30054307 pmcid: 6093727 doi: 10.1182/bloodadvances.2018019224
Quintana-Bustamante O, Lan-Lan Smith S, Griessinger E, Reyal Y, Vargaftig J, Lister TA, et al. Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis. Leukemia. 2012;26:1537–46.
pubmed: 22371011 pmcid: 3378638 doi: 10.1038/leu.2012.38
Wen XM, Hu JB, Yang J, Qian W, Yao DM, Deng ZQ, et al. CEBPA methylation and mutation in myelodysplastic syndrome. Med Oncol. 2015;32:192.
pubmed: 26025484 doi: 10.1007/s12032-015-0605-z
Gao Y, Jia M, Mao Y, Cai H, Jiang X, Cao X, et al. Distinct mutation landscapes between acute myeloid leukemia with myelodysplasia-related changes and de novo acute myeloid leukemia. Am J Clin Pathol. 2022;157:691–700.
pubmed: 34664628 doi: 10.1093/ajcp/aqab172
Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76.
pubmed: 25550361 pmcid: 4342352 doi: 10.1182/blood-2014-11-610543
Padella A, Simonetti G, Paciello G, Giotopoulos G, Baldazzi C, Righi S, et al. Novel and rare fusion transcripts involving transcription factors and tumor suppressor genes in acute myeloid leukemia. Cancers. 2019;11:1951.
Wang W, Beird H, Kroll CJ, Hu S, Bueso-Ramos CE, Fang H, et al. T(6;14)(q25;q32) involves BCL11B and is highly associated with mixed-phenotype acute leukemia, T/myeloid. Leukemia. 2020;34:2509–12.
pubmed: 32099038 doi: 10.1038/s41375-020-0761-9
Di Giacomo D, La Starza R, Gorello P, Pellanera F, Kalender Atak Z, De Keersmaecker K, et al. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia. Blood. 2021;138:773–84.
pubmed: 33876209 pmcid: 8513670 doi: 10.1182/blood-2021-150841
Montefiori LE, Bendig S, Gu Z, Chen X, Polonen P, Ma X, et al. Enhancer hijacking drives oncogenic BCL11B expression in lineage-ambiguous stem cell leukemia. Cancer Discov. 2021;11:2846–67.
Liu W, Hasserjian RP, Hu Y, Zhang L, Miranda RN, Medeiros LJ, et al. Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification. Mod Pathol. 2011;24:375–83.
pubmed: 21102413 doi: 10.1038/modpathol.2010.194
Wang SA, Hasserjian RP. Acute erythroleukemias, acute megakaryoblastic leukemias, and reactive mimics: a guide to a number of perplexing entities. Am J Clin Pathol. 2015;144:44–60.
pubmed: 26071461 doi: 10.1309/AJCPRKYAT6EZQHC7
Montalban-Bravo G, Benton CB, Wang SA, Ravandi F, Kadia T, Cortes J, et al. More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia. Blood. 2017;129:2584–7.
pubmed: 28246192 pmcid: 5418636 doi: 10.1182/blood-2016-11-749903
Wang W, Wang SA, Medeiros LJ, Khoury JD. Pure erythroid leukemia. Am J Hematol. 2017;92:292–6.
pubmed: 28006859 doi: 10.1002/ajh.24626
Mazzella FM, Smith D, Horn P, Cotelingam JD, Rector JT, Shrit MA, et al. Prognostic significance of pronormoblasts in erythrocyte predominant myelodysplastic patients. Am J Hematol. 2006;81:484–91.
pubmed: 16755568 doi: 10.1002/ajh.20563
Kowal-Vern A, Cotelingam J, Schumacher HR. The prognostic significance of proerythroblasts in acute erythroleukemia. Am J Clin Pathol. 1992;98:34–40.
pubmed: 1615923 doi: 10.1093/ajcp/98.1.34
Werstein B, Dunlap J, Cascio MJ, Ohgami RS, Fan G, Press R, et al. Molecular discordance between myeloid sarcomas and concurrent bone marrows occurs in actionable genes and is associated with worse overall survival. J Mol Diagn. 2020;22:338–45.
pubmed: 31866570 doi: 10.1016/j.jmoldx.2019.11.004
Greenland NY, Van Ziffle JA, Liu YC, Qi Z, Prakash S, Wang L. Genomic analysis in myeloid sarcoma and comparison with paired acute myeloid leukemia. Hum Pathol. 2021;108:76–83.
pubmed: 33232718 doi: 10.1016/j.humpath.2020.11.005
Engel NW, Reinert J, Borchert NM, Panagiota V, Gabdoulline R, Thol F, et al. Newly diagnosed isolated myeloid sarcoma-paired NGS panel analysis of extramedullary tumor and bone marrow. Ann Hematol. 2021;100:499–503.
pubmed: 33108522 doi: 10.1007/s00277-020-04313-x
Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100–11.
pubmed: 27923552 doi: 10.1016/S1470-2045(16)30626-X
Kuendgen A, Nomdedeu M, Tuechler H, Garcia-Manero G, Komrokji RS, Sekeres MA, et al. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS. Leukemia. 2021;35:835–49.
pubmed: 32595214 doi: 10.1038/s41375-020-0917-7
Schwaab J, Naumann N, Luebke J, Jawhar M, Somervaille TCP, Williams MS, et al. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. Am J Hematol. 2020;95:824–33.
pubmed: 32279331 doi: 10.1002/ajh.25825
Tang G, Sydney Sir Philip JK, Weinberg O, Tam W, Sadigh S, Lake JI, et al. Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study. Mod Pathol. 2019;32:490–8.
pubmed: 30401948 doi: 10.1038/s41379-018-0165-9
Yao J, Xu L, Aypar U, Meyerson HJ, Londono D, Gao Q, et al. Myeloid/lymphoid neoplasms with eosinophilia/ basophilia and ETV6-ABL1 fusion: cell-of-origin and response to tyrosine kinase inhibition. Haematologica. 2021;106:614–8.
pubmed: 32299902
Chen JA, Hou Y, Roskin KM, Arber DA, Bangs CD, Baughn LB, et al. Lymphoid blast transformation in an MPN with BCR-JAK2 treated with ruxolitinib: putative mechanisms of resistance. Blood Adv. 2021;5:3492–6.
pubmed: 34505882 pmcid: 8525236 doi: 10.1182/bloodadvances.2020004174
Carll T, Patel A, Derman B, Hyjek E, Lager A, Wanjari P, et al. Diagnosis and treatment of mixed phenotype (T-myeloid/lymphoid) acute leukemia with novel ETV6-FGFR2 rearrangement. Blood Adv. 2020;4:4924–8.
pubmed: 33049052 pmcid: 7556145 doi: 10.1182/bloodadvances.2019001282
Telford N, Alexander S, McGinn OJ, Williams M, Wood KM, Bloor A, et al. Myeloproliferative neoplasm with eosinophilia and T-lymphoblastic lymphoma with ETV6-LYN gene fusion. Blood Cancer J. 2016;6:e412.
pubmed: 27058227 pmcid: 4855251 doi: 10.1038/bcj.2016.11
Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, et al. The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature. 2018;562:373–9.
pubmed: 30209392 pmcid: 6195459 doi: 10.1038/s41586-018-0436-0
Montefiori LE, Mullighan CG. Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage. Best Pract Res Clin Haematol. 2021;34:101329.
pubmed: 34865701 doi: 10.1016/j.beha.2021.101329
van den Ancker W, Westers TM, de Leeuw DC, van der Veeken YF, Loonen A, van Beckhoven E, et al. A threshold of 10% for myeloperoxidase by flow cytometry is valid to classify acute leukemia of ambiguous and myeloid origin. Cytometry B Clin Cytom. 2013;84:114–8.
pubmed: 23325578 doi: 10.1002/cyto.b.21072
Guy J, Antony-Debre I, Benayoun E, Arnoux I, Fossat C, Le Garff-Tavernier M, et al. Flow cytometry thresholds of myeloperoxidase detection to discriminate between acute lymphoblastic or myeloblastic leukaemia. Br J Haematol. 2013;161:551–5.
pubmed: 23432206 doi: 10.1111/bjh.12277
Bras AE, Osmani Z, de Haas V, Jongen-Lavrencic M, te Marvelde JG, Zwaan CM, et al. Standardised immunophenotypic analysis of myeloperoxidase in acute leukaemia. Br J Haematol. 2021;193:922–7.
pubmed: 33161592 doi: 10.1111/bjh.17210
Lucas N, Duchmann M, Rameau P, Noel F, Michea P, Saada V, et al. Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia. Leukemia. 2019;33:2466–80.
pubmed: 30894665 doi: 10.1038/s41375-019-0447-3
Zalmai L, Viailly PJ, Biichle S, Cheok M, Soret L, Angelot-Delettre F, et al. Plasmacytoid dendritic cells proliferation associated with acute myeloid leukemia: phenotype profile and mutation landscape. Haematologica. 2021;106:3056–66.
pubmed: 33054115
Xiao W, Chan A, Waarts MR, Mishra T, Liu Y, Cai SF, et al. Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1-mutated acute myeloid leukemia. Blood. 2021;137:1377–91.
pubmed: 32871587 pmcid: 7955409 doi: 10.1182/blood.2020007897
Jaffe ES, Chan JKC. Histiocytoses converge through common pathways. Blood. 2022;139:157–9.
pubmed: 35024810 pmcid: 8759529 doi: 10.1182/blood.2021014529
Kemps PG, Picarsic J, Durham BH, Helias-Rodzewicz Z, Hiemcke-Jiwa L, van den Bos C, et al. ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood. 2022;139:256–80.
pubmed: 34727172 pmcid: 8759533 doi: 10.1182/blood.2021013338
McClain KL, Bigenwald C, Collin M, Haroche J, Marsh RA, Merad M, et al. Histiocytic disorders. Nat Rev Dis Primers. 2021;7:73.
pubmed: 34620874 doi: 10.1038/s41572-021-00307-9
Emile JF, Cohen-Aubart F, Collin M, Fraitag S, Idbaih A, Abdel-Wahab O, et al. Histiocytosis. Lancet. 2021;398:157–70.
pubmed: 33901419 doi: 10.1016/S0140-6736(21)00311-1
Salama HA, Jazieh AR, Alhejazi AY, Absi A, Alshieban S, Alzahrani M, et al. Highlights of the management of adult histiocytic disorders: langerhans cell histiocytosis, erdheim-chester disease, rosai-dorfman disease, and hemophagocytic lymphohistiocytosis. Clin Lymphoma Myeloma Leuk. 2021;21:e66–e75.
pubmed: 32943371 doi: 10.1016/j.clml.2020.08.007
Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019;567:521–4.
pubmed: 30867592 pmcid: 6438729 doi: 10.1038/s41586-019-1012-y
Chakraborty R, Abdel-Wahab O, Durham BH. MAP-kinase-driven hematopoietic neoplasms: a decade of progress in the molecular age. Cold Spring Harb Perspect Med. 2021;11:a034892.
Durham BH, Lopez Rodrigo E, Picarsic J, Abramson D, Rotemberg V, De Munck S, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25:1839–42.
pubmed: 31768065 pmcid: 6898787 doi: 10.1038/s41591-019-0653-6
Jacobsen E, Shanmugam V, Jagannathan J. Rosai-Dorfman disease with activating KRAS mutation - response to Cobimetinib. N Engl J Med. 2017;377:2398–9.
pubmed: 29236635 doi: 10.1056/NEJMc1713676
Chang KTE, Tay AZE, Kuick CH, Chen H, Algar E, Taubenheim N, et al. ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion. Mod Pathol. 2019;32:598–608.
pubmed: 30573850 doi: 10.1038/s41379-018-0168-6
Chan JK, Lamant L, Algar E, Delsol G, Tsang WY, Lee KC, et al. ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy. Blood. 2008;112:2965–8.
pubmed: 18660380 doi: 10.1182/blood-2008-03-147017
Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672–81.
pubmed: 26966089 pmcid: 5161007 doi: 10.1182/blood-2016-01-690636
Feldman AL, Arber DA, Pittaluga S, Martinez A, Burke JS, Raffeld M, et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood. 2008;111:5433–9.
pubmed: 18272816 pmcid: 2424145 doi: 10.1182/blood-2007-11-124792
Egan C, Lack J, Skarshaug S, Pham TA, Abdullaev Z, Xi L, et al. The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy. Mod Pathol. 2021;34:336–47.
pubmed: 32929178 doi: 10.1038/s41379-020-00673-x
Shao H, Xi L, Raffeld M, Feldman AL, Ketterling RP, Knudson R, et al. Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases. Mod Pathol. 2011;24:1421–32.
pubmed: 21666687 pmcid: 3175277 doi: 10.1038/modpathol.2011.102
Pericart S, Waysse C, Siegfried A, Struski S, Delabesse E, Laurent C, et al. Subsequent development of histiocytic sarcoma and follicular lymphoma: cytogenetics and next-generation sequencing analyses provide evidence for transdifferentiation of early common lymphoid precursor-a case report and review of literature. Virchows Arch. 2020;476:609–14.
pubmed: 31807922 doi: 10.1007/s00428-019-02691-w
Brunner P, Rufle A, Dirnhofer S, Lohri A, Willi N, Cathomas G, et al. Follicular lymphoma transformation into histiocytic sarcoma: indications for a common neoplastic progenitor. Leukemia. 2014;28:1937–40.
pubmed: 24850291 doi: 10.1038/leu.2014.167
Papo M, Diamond EL, Cohen-Aubart F, Emile JF, Roos-Weil D, Gupta N, et al. High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis. Blood. 2017;130:1007–13.
pubmed: 28679734 pmcid: 5570678 doi: 10.1182/blood-2017-01-761718
Durham BH, Roos-Weil D, Baillou C, Cohen-Aubart F, Yoshimi A, Miyara M, et al. Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood. 2017;130:176–80.
pubmed: 28566492 pmcid: 5510787 doi: 10.1182/blood-2016-12-757377
Cohen Aubart F, Roos-Weil D, Armand M, Marceau-Renaut A, Emile JF, Duployez N, et al. High frequency of clonal hematopoiesis in Erdheim-Chester disease. Blood. 2021;137:485–92.
pubmed: 33067622 pmcid: 8555377 doi: 10.1182/blood.2020005101
Dutzmann CM, Spix C, Popp I, Kaiser M, Erdmann F, Erlacher M, et al. Cancer in children with fanconi anemia and ataxia-telangiectasia-a nationwide register-based cohort study in Germany. J Clin Oncol. 2022;40:32–9.
pubmed: 34597127 doi: 10.1200/JCO.21.01495
Behrens YL, Göhring G, Bawadi R, Coktu S, Reimer C, Hoffmann B, et al. A novel classification of hematologic conditions in patients with Fanconi anemia. Haematologica. 2021;106:3000–3.
pubmed: 34196171 pmcid: 8561275
Cioc AM, Wagner JE, MacMillan ML, DeFor T, Hirsch B. Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics. Am J Clin Pathol. 2010;133:92–100.
pubmed: 20023263 doi: 10.1309/AJCP7W9VMJENZOVG
Gaipa G, Bugarin C, Cianci P, Sarno J, Bonaccorso P, Biondi A, et al. Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling. Blood Cancer J. 2015;5:e324.
pubmed: 26186557 pmcid: 4526778 doi: 10.1038/bcj.2015.52
Kim HS, Lee JW, Kang D, Yu H, Kim Y, Kang H, et al. Characteristics of RAS pathway mutations in juvenile myelomonocytic leukaemia: a single-institution study from Korea. Br J Haematol. 2021;195:748–56.
pubmed: 34590720 doi: 10.1111/bjh.17861
Stieglitz E, Taylor-Weiner AN, Chang TY, Gelston LC, Wang YD, Mazor T, et al. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet. 2015;47:1326–33.
pubmed: 26457647 pmcid: 4626387 doi: 10.1038/ng.3400
Bhoj EJ, Yu Z, Guan Q, Ahrens-Nicklas R, Cao K, Luo M, et al. Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing. Genet Med. 2017;19:715–8.
pubmed: 27763634 doi: 10.1038/gim.2016.169

Auteurs

Joseph D Khoury (JD)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jkhoury@unmc.edu.
ORCID: 0000-0003-2621-3584

Eric Solary (E)

Department of Hematology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France. eric.solary@gustaveroussy.fr.
ORCID: 0000-0002-8629-1341

Oussama Abla (O)

Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.

Yassmine Akkari (Y)

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
ORCID: 0000-0002-3072-7388

Rita Alaggio (R)

Pathology Unit, Department of Laboratories, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.

Jane F Apperley (JF)

Centre for Haematology, Imperial College London, London, UK.
ORCID: 0000-0002-1710-1794

Rafael Bejar (R)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
ORCID: 0000-0002-5603-4598

Emilio Berti (E)

University of Milan, Fondazione Cà Granda, IRCCS, Ospedale Maggiore Policlinico, Milano, Italy.

Lambert Busque (L)

Service d'hématologie, oncologie et transplantation, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada.
ORCID: 0000-0002-5375-3749

John K C Chan (JKC)

Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.

Weina Chen (W)

Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
ORCID: 0000-0001-5638-4371

Xueyan Chen (X)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Wee-Joo Chng (WJ)

Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore.

John K Choi (JK)

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
ORCID: 0000-0002-2861-0180

Isabel Colmenero (I)

Department of Pathology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
ORCID: 0000-0001-6859-187X

Sarah E Coupland (SE)

Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool, UK.

Nicholas C P Cross (NCP)

Faculty of Medicine, University of Southampton, Southampton, UK.
ORCID: 0000-0001-5481-2555

Daphne De Jong (D)

Amsterdam UMC, Location Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam, The Netherlands.

M Tarek Elghetany (MT)

Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.

Emiko Takahashi (E)

Department of Pathology, Aichi Medical University Hospital, Nagakute, Japan.
ORCID: 0000-0001-8284-567X

Jean-Francois Emile (JF)

Department of Pathology, Ambroise Pare Hospital, AP-HP and Versailles SQY University, Boulogne, France.
ORCID: 0000-0002-6073-4466

Judith Ferry (J)

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Linda Fogelstrand (L)

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg and Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.

Michaela Fontenay (M)

Laboratory of Hematology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital and Université Paris Cité, CNRS, INSERM, Cochin Institute, Paris, France.

Ulrich Germing (U)

Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.

Sumeet Gujral (S)

Department of Pathology, Tata Memorial Hospital, Mumbai, India.

Torsten Haferlach (T)

MLL Munich Leukemia Laboratory, Munich, Germany.
ORCID: 0000-0003-0196-2837

Claire Harrison (C)

Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK.

Jennelle C Hodge (JC)

Indiana University School of Medicine, Indianapolis, IN, USA.

Shimin Hu (S)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0001-7110-3814

Joop H Jansen (JH)

Lab Hematology, Dept LABGK, Radboud University Medical Center, Nijmegen, The Netherlands.

Rashmi Kanagal-Shamanna (R)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0001-7829-5249

Hagop M Kantarjian (HM)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0002-1908-3307

Christian P Kratz (CP)

Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
ORCID: 0000-0003-4120-5873

Xiao-Qiu Li (XQ)

Departments of Pathology and Oncology, Fudan University, Shanghai, China.

Megan S Lim (MS)

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Keith Loeb (K)

Section of Pathology, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Sanam Loghavi (S)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0001-8980-3202

Andrea Marcogliese (A)

Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.

Soheil Meshinchi (S)

Pediatric Hematology and Oncology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Phillip Michaels (P)

Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Kikkeri N Naresh (KN)

Section of Pathology, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
ORCID: 0000-0003-3807-3638

Yasodha Natkunam (Y)

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0002-9816-1018

Reza Nejati (R)

Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.

German Ott (G)

Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Eric Padron (E)

Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
ORCID: 0000-0002-4707-7916

Keyur P Patel (KP)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nikhil Patkar (N)

Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, India.
ORCID: 0000-0001-9234-2857

Jennifer Picarsic (J)

Pathology and Lab Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Uwe Platzbecker (U)

Department of Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.
ORCID: 0000-0003-1863-3239

Irene Roberts (I)

Department of Paediatrics, University of Oxford, Oxford, UK.

Anna Schuh (A)

Department of Oncology, University of Oxford, Oxford, UK.
ORCID: 0000-0002-3938-8490

William Sewell (W)

Immunology Division, Garvan Institute of Medical Research, Sydney, Australia.

Reiner Siebert (R)

Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.

Prashant Tembhare (P)

Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, India.
ORCID: 0000-0002-9030-0415

Jeffrey Tyner (J)

Cell, Developmental & Cancer Biology Department, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
ORCID: 0000-0002-2133-0960

Srdan Verstovsek (S)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0002-6912-8569

Wei Wang (W)

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0001-6821-4556

Brent Wood (B)

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Wenbin Xiao (W)

Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
ORCID: 0000-0001-8586-8500

Cecilia Yeung (C)

Section of Pathology, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
ORCID: 0000-0001-6799-2022

Andreas Hochhaus (A)

Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany. andreas.hochhaus@med.uni-jena.de.
ORCID: 0000-0003-0626-0834

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Classifications MeSH

questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Tumeurs hématologiques › The 5th edition of the World Health...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Maladies lymphatiques › Histiocytose › The 5th edition of the World Health...
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