The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
Open accessAbstract
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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A recent proposal suggested normalizing BST value by dividing it by the number of extra copies of the TPSAB1 gene plus one.
“A recent proposal (10), also received by the 5th WHO classification (8), suggested normalizing BST value by dividing it by the number of extra copies of the TPSAB1 gene, encoding alpha tryptase, plus one.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section says basal serum tryptase should be adjusted in hereditary alpha-tryptasaemia, supporting the statement that the WHO classification recognizes an adjustment. It does not specify TPSAB1 copy number or the proposed division-by-extra-copies-plus-one formula (searched: TPSAB1, hereditary alpha-tryptasaemia adjustment, and the division formula). (LLM, conf=0.86)
Experimental — accuracy not yet measuredBST above 20 ng/ml is a minor criterion for diagnosis of SM according to WHO and ICC.
“Basal serum tryptase (BST) above 20 ng/ml represents a minor criterion according to WHO and ICC for the diagnosis of systemic mastocytosis (SM)”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section states that basal serum tryptase >20 ng/ml is a minor criterion for systemic mastocytosis in the WHO classification, with adjustment in cases of hereditary alpha-tryptasaemia. This WHO paper does not establish the claim about ICC criteria. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSM is categorized into five distinct subtypes: indolent (ISM), smoldering (SSM), aggressive (ASM), associated to another haematological/myeloid neoplasm (SM-AHN), and mast cell leukemia (MCL).
“SM was categorized into five distinct subtypes: indolent (ISM), smoldering (SSM), aggressive (ASM), associated to another haematological/myeloid neoplasm (SM-AHN), and mast cell leukemia (MCL).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section (Table 2) lists all five named systemic mastocytosis subtypes, but it also lists bone marrow mastocytosis. The accompanying text explicitly says bone marrow mastocytosis is now a separate SM subtype, so the claim that there are five distinct subtypes is incomplete. (LLM, conf=0.90)
Experimental — accuracy not yet measuredB-findings have been slightly modified: WHO embedded a VAF >10% of KIT D816V; ICC simplified definition of cytopenia or cytosis.
“B-findings have been slightly modified, as WHO has embedded a variant allele frequency (VAF) >10% of the KIT D816V variant (8), and ICC has simplified the definition of cytopenia (not meeting the criteria for C-findings) or cytosis (7).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section says WHO refined the B-findings to include KIT D816V with a variant allele frequency of ≥10% in bone marrow cells or peripheral blood leukocytes. The citing sentence says >10%, which excludes exactly 10%; its separate ICC statement is attributed to another citation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWell-differentiated SM (WDSM) is not recognized as an independent subtype according to 2022 ICC and WHO 5th Edition.
“Well-differentiated SM (WDSM) is a variant of systemic mastocytosis not recognized as an independent subtype according to 2022 ICC and WHO 5th Edition.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section classifies WDSM as a morphologic variant that can occur in any systemic mastocytosis subtype, rather than as an independent WHO subtype. This paper describes the WHO 5th edition; the cited passages do not establish the claim about the 2022 ICC. (LLM, conf=0.85)
Experimental — accuracy not yet measured
B and C findings reflect burden of disease and organ impairment, respectively, and are key for subclassification of SM clinical variants.
“B and C findings reflect the burden of the disease and organ impairment, respectively, and continue to be the key for establishing an accurate subclassification of SM clinical variants.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section calls B-findings measures of ‘burden of disease’ and uses their absence to characterize the bone marrow mastocytosis subtype. It describes C-findings as ‘cytoreduction-requiring,’ but does not explicitly equate them with organ impairment or state that both sets of findings are key to subclassifying SM variants. (LLM, conf=0.83)
Experimental — accuracy not yet measuredWHO 2022 and ICC define biallelic/multihit mTP53 MDS as discrete entities, and both systems may significantly underrecognize this entity.
“the updated World Health Organization (WHO) 2022 criteria and the 2022 International Consensus Classification (ICC) define biallelic/multihit mTP53 MDS as discrete entities, although with heterogeneity in classification, and notably, both systems may significantly underrecognize this entity.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [14]
The ‘MDS with defining genetic abnormalities’ section and Table 3 identify MDS with biallelic TP53 inactivation as a WHO disease type. The cited paper does not establish how the ICC classifies it or support the assertion that both systems may significantly underrecognize it. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn 2022 the WHO revised the classification of disease phase in CML, omitting the concept of accelerated phase and defining blast phase as the presence of >20% blasts.
“In 2022 the WHO revised the classification of disease phase in CML, omitting the concept of AP, and defining BP as the presence of >20% blasts [14].”
From 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia (2025) · cites this paper as [14]
The CML section says the 2022 classification omits accelerated phase, supporting that part of the claim. It defines blast phase using ≥20% myeloid blasts—not >20%—and also lists extramedullary blast proliferation and increased lymphoblasts as criteria. (LLM, conf=0.92)
Experimental — accuracy not yet measuredThe aberrant MC phenotype now includes CD30 expression beside positivity of CD2 and/or CD25.
“The aberrant MC phenotype now includes also CD30 expression beside the positivity of CD2 and/or CD25.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
C-findings remained essentially unchanged.
“While C-findings remained essentially unchanged”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
Classification and diagnostic criteria of SM were recently refined by the 2022 ICC and WHO 5th edition.
“Classification and diagnostic criteria of SM were recently refined by the 2022 International Consensus Classification (ICC) (7) and the 5th edition of the World Health Organization (WHO) classification (8)”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
In WHO classification, BST value should be adjusted in case of HαT, if known.
“in the WHO classification, its value should be adjusted in case of HαT, if known”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The presence of any KIT-activating variants, in addition to canonical D816V, has been considered in minor criteria.
“The presence of any KIT-activating variants, in addition to the canonical D816V, has also been considered.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
Both classifications defined bone marrow mastocytosis (BMM), a separate variant according to WHO and a subtype of ISM according to ICC.
“both classifications have defined bone marrow mastocytosis (BMM), a separate variant according to the WHO (8) and a subtype of ISM according to the ICC (7).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
Demonstration of multifocal infiltrates of tryptase- or CD117-positive MCs (≥15 mast cells in aggregates) in BM or other extracutaneous organs remained the major diagnostic criterion.
“Demonstration of multifocal infiltrates of tryptase- or CD117-positive MCs (≥15 mast cells in aggregates) in BM or other extracutaneous organs remained the major diagnostic criterion.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section (page unavailable) discusses revised minor criteria for systemic mastocytosis but does not state the claimed major criterion. Searches for multifocal mast-cell infiltrates, the ≥15-cell threshold, and tryptase or CD117 did not locate a passage establishing those details in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredWHO requires one major and one minor criterion, or three minor criteria, for a full SM diagnosis.
“While the WHO (8) requires one major and one minor criterion, or three minor criteria”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [8]
The Mastocytosis section identifies several minor criteria for systemic mastocytosis but does not state how many major or minor criteria are required for diagnosis. Searches for the claimed one-major-plus-one-minor and three-minor combinations found no passage establishing either rule in our copy; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Khoury, J. D., Solary, E., Abla, O., Akkari, Y., Alaggio, R., Apperley, J. F., Bejar, R., Berti, E., Busque, L., Chan, J. K. C., Chen, W., Chen, X., Chng, W.-J., Choi, J. K., Colmenero, I., Coupland, S. E., Cross, N. C. P., De Jong, D., Elghetany, M. T., Takahashi, E., Emile, J.-F., Ferry, J., Fogelstrand, L., Fontenay, M., Germing, U., Gujral, S., Haferlach, T., Harrison, C., Hodge, J. C., Hu, S., Jansen, J. H., Kanagal-Shamanna, R., Kantarjian, H. M., Kratz, C. P., Li, X.-Q., Lim, M. S., Loeb, K., Loghavi, S., Marcogliese, A., Meshinchi, S., Michaels, P., Naresh, K. N., Natkunam, Y., Nejati, R., Ott, G., Padron, E., Patel, K. P., Patkar, N., Picarsic, J., Platzbecker, U., Roberts, I., Schuh, A., Sewell, W., Siebert, R., Tembhare, P., Tyner, J., Verstovsek, S., Wang, W., Wood, B., Xiao, W., Yeung, C., & Hochhaus, A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Hospital for Sick Children (CA)
- Nationwide Children's Hospital (US)
- Bambino Gesù Children's Hospital (IT)
- Imperial College London (GB)
- University of California San Diego (US)
- University of Milan (IT)
- Hôpital Maisonneuve-Rosemont (CA)
- Queen Elizabeth Hospital (CN)
- The University of Texas Southwestern Medical Center (US)
- University of Washington (US)
- National University Cancer Institute, Singapore (SG)
- University of Alabama at Birmingham (US)
- Hospital Infantil Universitario Niño Jesús (ES)
- Liverpool University Hospitals NHS Foundation Trust (GB)
- University of Southampton (GB)
- Baylor College of Medicine (US)
- Aichi Medical University (JP)
- Harvard University (US)
- Sahlgrenska University Hospital (SE)
- Heinrich Heine University Düsseldorf (DE)
- Tata Memorial Hospital (IN)
- Munich Leukemia Laboratory (Germany) (DE)
- St Thomas' Hospital (GB)
- Indiana University School of Medicine (US)
- Radboud University Medical Center (NL)
- Medizinische Hochschule Hannover (DE)
- University of Pennsylvania (US)
- Fred Hutch Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- Stanford Medicine (US)
- Fox Chase Cancer Center (US)
- Robert Bosch Hospital (DE)
- Moffitt Cancer Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- University Hospital Leipzig (DE)
- University of Oxford (GB)
- Garvan Institute of Medical Research (AU)
- Universität Ulm (DE)
- Oregon Health & Science University (US)
- Children's Hospital Los Angeles (US)
- Memorial Sloan Kettering Cancer Center (US)
- Jena University Hospital (DE)
- Corresponding author
- Khoury, Joseph D.
- Hochhaus, Andreas
- ORCID
- Khoury, Joseph D.
- Solary, Eric
- Abla, Oussama
- Akkari, Yassmine
- Alaggio, Rita
- Apperley, Jane F.
- Bejar, Rafael
- Berti, Emilio
- Busque, Lambert
- Chen, Weina
- Chen, Xueyan
- Chng, Wee-Joo
- Choi, John K.
- Colmenero, Isabel
- Coupland, Sarah E.
- Cross, Nicholas C. P.
- Elghetany, M. Tarek
- Takahashi, Emiko
- Emile, Jean-Francois
- Ferry, Judith
- Fogelstrand, Linda
- Germing, Ulrich
- Gujral, Sumeet
- Haferlach, Torsten
- Harrison, Claire
- Hodge, Jennelle C.
- Hu, Shimin
- Jansen, Joop H.
- Kanagal-Shamanna, Rashmi
- Kantarjian, Hagop M.
- Kratz, Christian P.
- Lim, Megan S.
- Loeb, Keith
- Loghavi, Sanam
- Marcogliese, Andrea
- Meshinchi, Soheil
- Michaels, Phillip
- Naresh, Kikkeri N.
- Natkunam, Yasodha
- Nejati, Reza
- Ott, German
- Padron, Eric
- Patel, Keyur P.
- Patkar, Nikhil
- Picarsic, Jennifer
- Platzbecker, Uwe
- Roberts, Irene
- Schuh, Anna
- Sewell, William
- Siebert, Reiner
- Tembhare, Prashant
- Tyner, Jeffrey
- Verstovsek, Srdan
- Wang, Wei
- Wood, Brent
- Xiao, Wenbin
- Yeung, Cecilia
- Hochhaus, Andreas
- Venue
- Leukemia
- Published
- 2022-06-22
- Volume
- 36
- Issue
- 7
- Pages
- 1703-1719
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC9252913
- OpenAlex
- W4283271244
- Cited by
- 4,274
- References
- 117
- Citations by year
- 2026: 882 · 2025: 1133 · 2024: 1131 · 2023: 925 · 2022: 194 · 2019: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 150.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Leukemia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- ePrints Soton (University of Southampton) (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Qucosa (Saxon State and University Library Dresden) (submittedVersion, cc-by)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- National University of Singapore (submittedVersion)
- HAL (submittedVersion, cc-by)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Common Library Network (Der Gemeinsame Bibliotheksverbund) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Massachusetts General Hospital
- Children's Hospital Los Angeles
- University of Pennsylvania
- Memorial Sloan-Kettering Cancer Center
- Texas Children's Hospital
- Cincinnati Children's Hospital Medical Center
- Nationwide Children's Hospital
- University of Washington
- University of Texas Southwestern Medical Center
- University of Alabama at Birmingham
- Centre International de Recherche sur le Cancer
- Moffitt Cancer Center
- Wellcome Trust
- University of Alabama
- Università degli Studi di Milano
- Amsterdam University Medical Centers
- National Institute for Health and Care Research (NF-SI-0617-10126, NF-SI-0611-10275)
- University of Southampton
- Imperial College London
- University of Oxford
- Institut National de la Santé et de la Recherche Médicale
- Radboud Universiteit
- Vrije Universiteit Amsterdam
- Fudan University
- Centre National de la Recherche Scientifique
- Université de Montréal
- Medizinischen Hochschule Hannover
- Sahlgrenska Universitetssjukhuset
- Göteborgs Universitet
- Hospital for Sick Children
- Radboud Universitair Medisch Centrum
- Université Paris-Saclay
- Universitätsklinikum Jena
- Institut Gustave-Roussy
- Universität Ulm
- Assistance publique-Hôpitaux de Paris
- National University Cancer Institute, Singapore
- School of Medicine, Stanford University
- University of Texas MD Anderson Cancer Center
- University of California, San Diego
- School of Medicine, Indiana University
- Department of Laboratory Medicine and Pathology, University of Washington
- Knight Cancer Institute, Oregon Health and Science University
- Sahlgrenska Akademin
- National Cancer Institute (P30CA008748, K08CA267058)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Physiology › Histiocytic Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- myeloid neoplasms, tumor classification, diagnostic criteria, prognostic factors, therapeutic biomarkers, molecular classification, hematologic malignancies
- MeSH terms
- Humans, World Health Organization, Histiocytosis, Hematologic Neoplasms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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