The World Health Organization (WHO) classification of haematolymphoid tumors is the most widely used pathologic classification system for hematopoietic and lymphoid neoplasms. The 5^th edition ¹ was published in 2022 and supersedes the 4^th edition revised published in 2016.

Classification

Myeloid proliferations and neoplasms

Myeloid precursor lesion

• clonal hematopoiesis

• clonal cytopenias of undetermined significance

Myeloproliferative neoplasms

• myeloproliferative neoplasms

  • chronic myeloid leukemia

  • chronic neutrophilic leukemia

  • chronic eosinophilic leukemia

  • polycythemia vera

  • essential thrombocythemia

  • primary myelofibrosis

  • juvenile myelomonocytic leukemia

  • myeloproliferative neoplasm, NOS

Mastocytosis

• mastocytosis

  • cutaneous mastocytosis

  • systemic mastocytosis

  • mast cell sarcoma

Myelodysplastic neoplasms

• myelodysplastic neoplasms, with defining genetic abnormalities

  • myelodysplastic neoplasm with low blasts and 5q deletion

  • myelodysplastic neoplasm with low blasts and SF3B1 mutation

  • myelodysplastic neoplasm with biallelic TP53 inactivation

• myelodysplastic neoplasms, morphologically defined

  • myelodysplastic neoplasm with low blasts

  • myelodysplastic neoplasm, hypoplastic

  • myelodysplastic neoplasm with increased blasts

• myelodysplastic neoplasms of childhood

  • childhood myelodysplastic neoplasm with low blasts

  • childhood myelodysplastic neoplasm with increased blasts

Myelodysplastic/myeloproliferative neoplasms

• myelodysplastic/myeloproliferative neoplasms

  • chronic myelomonocytic leukemia

  • myelodysplastic/myeloproliferative neoplasm with neutrophilia

  • myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis

  • myelodysplastic/myeloproliferative neoplasm, NOS

Acute myeloid leukemia

• acute myeloid leukemia with defining genetic abnormalities

  • acute promyelocytic leukemia with PML::RARA fusion

  • acute myeloid leukemia with RUNX1::RUNX1T1 fusion

  • acute myeloid leukemia with CBFB::MYH11 fusion

  • acute myeloid leukemia with DEK::NUP214 fusion

  • acute myeloid leukemia with RBM15::MRTFA fusion

  • acute myeloid leukemia with BCR::ABL1 fusion

  • acute myeloid leukemia with KMT2A rearrangement

  • acute myeloid leukemia with MECOM rearrangement

  • acute myeloid leukemia with NUP98 rearrangement

  • acute myeloid leukemia with NPM1 mutation

  • acute myeloid leukemia with CEBPA mutation

  • acute myeloid leukemia, myelodysplasia-related

  • acute myeloid leukemia with other defined genetic alterations

• acute myeloid leukemia, defined by differentiation

  • acute myeloid leukemia with minimal differentiation

  • acute myeloid leukemia without maturation

  • acute myeloid leukemia with maturation

  • acute basophilic leukemia

  • acute myelomonocytic leukemia

  • acute monocytic leukemia

  • acute erythroid leukemia

  • acute megakaryoblastic leukemia

• myeloid sarcoma

Myeloid neoplasms, secondary

• myeloid neoplasm post cytotoxic therapy

• myeloid neoplasms associated with germline predisposition

• myeloid proliferations associated with Down syndrome

Myeloid/lymphoid neoplasms

• myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement

  • myeloid/lymphoid neoplasms with PDGFRA rearrangement

  • myeloid/lymphoid neoplasms with PDGFRB rearrangement

  • myeloid/lymphoid neoplasms with FGFR1 rearrangement

  • myeloid/lymphoid neoplasms with JAK2 rearrangement

  • myeloid/lymphoid neoplasm with FLT3 rearrangement

  • myeloid/lymphoid neoplasm with ETV6::ABL1 fusion

  • myeloid/lymphoid neoplasms with other tyrosine kinase gene fusions

Acute leukaemias of mixed or ambiguous lineage

• acute leukemia of ambiguous lineage with defining genetic abnormalities

  • mixed-phenotype acute leukemia with BCR::ABL1 fusion

  • mixed-phenotype acute leukemia with KMT2A rearrangement

  • acute leukemia of ambiguous lineage with other defined genetic alterations

• acute leukemia of ambiguous lineage, immunophenotypically defined

  • mixed-phenotype acute leukemia, B/myeloid

  • mixed-phenotype acute leukemia, T/myeloid

  • mixed-phenotype acute leukemia, rare types

  • acute leukemia of ambiguous lineage, NOS

  • acute undifferentiated leukemia

Histiocytic / dendritic cell neoplasms

Plasmacytoid dendritic cell neoplasms

• plasmacytoid dendritic cell neoplasms

  • mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm

  • blastic plasmacytoid dendritic cell neoplasm

Langerhans cell and other dendritic cell neoplasms

• Langerhans cells neoplasms

  • Langerhans cell histiocytosis

  • Langerhans cell sarcoma

• other dendritic cell neoplasms

  • indeterminate dendritic cell tumor

  • interdigitating dendritic cell sarcoma

Histiocyte/macrophage neoplasms

• histiocytic neoplasms

  • juvenile xanthogranuloma

  • Erdheim-Chester disease

  • Rosai-Dorfman Disease

  • ALK-positive histiocytosis

  • histiocytic sarcoma

B-cell lymphoid proliferations and lymphomas

Tumor-like lesions with B-cell predominance

• reactive B-cell rich lymphoid proliferations that can mimic lymphoma

• IgG4-related disease

• unicentric Castleman disease

• idiopathic multicentric Castleman disease

• KSHV/HHV8-associated multicentric Castleman disease

Precursor B-cell neoplasms

• B-lymphoblastic leukaemias/lymphomas

  • B-lymphoblastic leukemia/lymphoma

  • B-lymphoblastic leukemia/lymphoma with high hyperdiploidy

  • B-lymphoblastic leukemia/lymphoma with hypodiploidy

  • B-lymphoblastic leukemia/lymphoma with iAMP21

  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion

  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features

  • B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement

  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion

  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features

  • B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion

  • B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion

  • B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion

  • B-lymphoblastic leukemia/lymphoma with other defined genetic alterations

  • B-lymphoblastic leukemia/lymphoma, NOS

Mature B-cell neoplasms

• pre-neoplastic and neoplastic small lymphocytic proliferations

  • monoclonal B-cell lymphocytosis

  • chronic lymphocytic leukemia / small lymphocytic lymphoma

• splenic B-cell lymphomas and leukaemias

  • hairy cell leukemia

  • splenic marginal zone lymphoma

  • splenic diffuse red pulp small B-cell lymphoma

  • splenic B-cell lymphoma/leukemia with prominent nucleoli

• lymphoplasmacytic lymphoma

• marginal zone lymphoma

  • extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

  • primary cutaneous marginal zone lymphoma

  • nodal marginal zone lymphoma

  • pediatric nodal marginal zone lymphoma

• follicular lymphoma

  • in situ follicular B-cell neoplasm

  • follicular lymphoma

  • pediatric-type follicular lymphoma

  • duodenal-type follicular lymphoma

• cutaneous follicle center lymphoma

  • primary cutaneous follicle center lymphoma

• mantle cell lymphoma

  • in situ mantle cell neoplasm

  • mantle cell lymphoma

  • leukemic non-nodal mantle cell lymphoma

• transformations of indolent B-cell lymphomas

• large B-cell lymphomas

  • diffuse large B-cell lymphoma, NOS

  • T-cell/histiocyte-rich large B-cell lymphoma

  • diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements

  • ALK-positive large B-cell lymphoma

  • large B-cell lymphoma with IRF4 rearrangement

  • high-grade B-cell lymphoma with 11q aberrations

  • lymphomatoid granulomatosis

  • EBV-positive diffuse large B-cell lymphoma

  • diffuse large B-cell lymphoma associated with chronic inflammation

  • fibrin-associated large B-cell lymphoma

  • fluid overload-associated large B-cell lymphoma

  • plasmablastic lymphoma

  • primary large B-cell lymphoma of immune-privileged sites

  • primary cutaneous diffuse large B-cell lymphoma, leg type

  • intravascular large B-cell lymphoma

  • primary mediastinal large B-cell lymphoma

  • mediastinal grey zone lymphoma

  • high-grade B-cell lymphoma, NOS

• Burkitt lymphoma

• KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas

  • primary effusion lymphoma

  • KSHV/HHV8-positive diffuse large B-cell lymphoma

  • KSHV/HHV8-positive germinotropic lymphoproliferative disorder

• lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation

  • hyperplasias arising in immune deficiency/dysregulation

  • polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation

  • EBV-positive mucocutaneous ulcer

  • lymphomas arising in immune deficiency/dysregulation

  • inborn error of immunity-associated lymphoid proliferations and lymphomas

Hodgkin lymphoma

• classic Hodgkin lymphoma

• nodular lymphocyte predominant Hodgkin lymphoma

Plasma cell neoplasms and other diseases with paraproteins

• monoclonal gammopathies

  • cold agglutinin disease

  • IgM monoclonal gammopathy of undetermined significance

  • non-IgM monoclonal gammopathy of undetermined significance

  • monoclonal gammopathy of renal significance

• diseases with monoclonal immunoglobulin deposition

  • immunoglobulin-related (AL) amyloidosis

  • monoclonal immunoglobulin deposition disease

• heavy chain diseases

  • mu heavy chain disease

  • gamma heavy chain disease

  • alpha heavy chain disease

• plasma cell neoplasms

  • plasmacytoma

  • plasma cell myeloma / multiple myeloma

  • plasma cell neoplasms with associated paraneoplastic syndrome

T-cell and NK-cell lymphoid proliferations and lymphomas

Tumor-like lesions with T-cell predominance

• Kikuchi-Fujimoto disease

• autoimmune lymphoproliferative syndrome

• indolent T-lymphoblastic proliferation

Precursor T-cell neoplasms

• T-lymphoblastic leukemia/lymphoma, NOS

• early T-precursor lymphoblastic leukemia/lymphoma

Mature T-cell and NK-cell neoplasms

• mature T-cell and NK-cell leukaemias

  • T-prolymphocytic leukemia

  • T-large granular lymphocytic leukemia

  • NK-large granular lymphocytic leukemia

  • adult T-cell leukemia/lymphoma

  • Sézary syndrome

  • aggressive NK-cell leukemia

• primary cutaneous T-cell lymphoid proliferations and lymphomas

  • primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder

  • primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder

  • mycosis fungoides

  • primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis

  • primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma

  • subcutaneous panniculitis-like T-cell lymphoma

  • primary cutaneous gamma/delta T-cell lymphoma

  • primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

  • primary cutaneous peripheral T-cell lymphoma, NOS

• intestinal T-cell and NK-cell lymphoid proliferations and lymphomas

  • indolent T-cell lymphoma of the gastrointestinal tract

  • indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract

  • enteropathy-associated T-cell lymphoma

  • monomorphic epitheliotropic intestinal T-cell lymphoma

  • intestinal T-cell lymphoma, NOS

• hepatosplenic T-cell lymphoma

• anaplastic large cell lymphoma

  • ALK-positive anaplastic large cell lymphoma

  • ALK-negative anaplastic large cell lymphoma

  • breast implant-associated anaplastic large cell lymphoma

• nodal T-follicular helper (TFH) cell lymphoma

  • nodal TFH cell lymphoma, angioimmunoblastic-type

  • nodal TFH cell lymphoma, follicular-type

  • nodal TFH cell lymphoma, NOS

• peripheral T-cell lymphoma, NOS

• EBV-positive NK-cell and T-cell lymphomas

  • EBV-positive nodal T- and NK-cell lymphoma

  • extranodal NK/T-cell lymphoma

• EBV-positive T-cell and NK-cell lymphoid proliferations and lymphomas of childhood

  • severe mosquito bite allergy

  • hydroa vacciniforme lymphoproliferative disorder

  • systemic chronic active EBV disease

  • systemic EBV-positive T-cell lymphoma of childhood

Stroma-derived neoplasms of lymphoid tissues

Mesenchymal dendritic cell neoplasms

• follicular dendritic cell sarcoma

• EBV-positive inflammatory follicular dendritic cell sarcoma

• fibroblastic reticular cell tumor

Myofibroblastic tumors

• intranodal palisaded myofibroblastoma

Spleen-specific vascular-stromal tumors

• littoral cell angioma

• splenic hamartoma

• sclerosing angiomatoid nodular transformation (SANT) of spleen

Genetic tumor syndromes

• Fanconi anemia

• Bloom syndrome

• ataxia-telangiectasia syndrome

• RASopathies

Changes from prior versions

The classification follows the Human Genome Organization Gene Nomenclature Committee recommendations which includes the designation of gene fusions using double colons (::) ².

"Tumor-like" lesions are a category. This is grouped into lesions with B-cell predominance (which includes the additions Castleman disease and IgG4-related disease) and lesions with T-cell predominance.

Lymphoproliferative disorders and lymphomas associated with primary immunodeficiencies and HIV have been regrouped within the "lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation" category, which is itself classified under "mature B-cell neoplasms". Similarly post-transplant lymphoproliferative disorders (PTLD) is no longer a separate classification and is now encompassed within the same group. These changes aim to shift the focus from the disease background to the histologic and pathogenetic features that they share ³.

Two other entities have been removed:

• B-cell prolymphocytic leukemia

• NK-lymphoblastic leukemia/lymphoma

A category of stroma-derived neoplasms unique to the lymph node and spleen has been included (soft tissue tumors not specific to the lymph node or spleen such as hemangioma or angiosarcoma are covered in the WHO classification of soft tissue tumors).