WHO Classification 5th Edition

WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND

LYMPHOID TISSUES
Overview of the Upcoming 5th Edition1 ,2

Simplified List
Myeloid Neoplasms
1. Clonal haemotopoiesis
2. Myeloproliferative neoplasms
a. Chronic myeloid leukaemia
b. Polycythaemia vera
c. Essential thrombocythaemia
d. Primary myelofibrosis (PMF)
- Prefibrotic/early PMF
- Overt fibrotic PMF
e. Chronic neutrophilic leukaemia
f. Chronic eosinophilic leukaemia
g. Juvenile myelomonocytic leukaemia
h. Myeloproliferative neoplasm, unclassifiable
3. Mastocytosis
4. Myelodysplastic neoplasms (MDS)
5. Myelodysplastic/myeloproliferative neoplasms
6. Acute myeloid leukaemia (AML) & related neoplasms
a. AML with defining genetic abnormalities
- Acute promyelocytic leukaemia with PML::RARA fusion
- AML with other defined genetic alterations
b. AML, defined by differentiation
- AML with minimal differentiation
- AML without maturation
- AML with maturation
- Acute myelomonocytic leukaemia
- Acute monocytic leukaemia
- Acute erythroid leukaemia
- Acute megakaryoblastic leukaemia
- Acute basophilic leukaemia
c. Myeloid sarcoma
d. Myeloid proliferations related to Down syndrome
7. Secondary myeloid neoplasms
8. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions
9. Acute leukaemias of mixed or ambiguous lineage
10. Histiocytic/dendritic cell neoplasms

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 WHO Classification 5th Edition

Lymphoid Neoplasms
B-cell lymphoid proliferations and lymphomas
1. Tumour-like lesions with B-cell predominance
2. Precursor B-cell neoplasms
3. Mature B-cell neoplasms
a. Pre-neoplastic and neoplastic small lymphocytic proliferations
- Monoclonal B-cell lymphocytosis (MBL)
- Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL)
b. Splenic B-cell lymphomas and leukaemias
c. Lymphoplasmacytic lymphoma
d. Marginal zone lymphoma
e. Follicular lymphoma
f. Cutaneous follicle centre lymphoma
g. Mantle cell lymphoma
h. Transformations of indolent B-cell lymphomas
i. Large B-cell lymphomas
j. Burkitt lymphoma
k. KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas
l. Lymphoid proliferations and lymphomas associated with immune deficiency and
dysregulation
m. Hodgkin lymphoma
- Classical Hodgkin lymphoma
- Nodular lymphocyte predominant Hodgkin lymphoma
4. Plasma cell neoplasms and other diseases with paraproteins
a. Monoclonal gammopathies
b. Diseases with monoclonal immunoglobulin deposition
c. Heavy chain disease
d. Plasma cell neoplasms
- Plasmacytoma
- Plasma cell myeloma
- Plasma cell neoplasms with associated paraneoplastic syndrome

T-cell and NK-cell lymphoid proliferations and lymphomas

1. Tumour-like lesions with T-cell predominance
2. Precursor T-cell neoplasms
3. Mature T- & NK-cell neoplasms

Stroma-derived neoplasms of lymphoid tissues

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 WHO Classification 5th Edition

Complete List
Myeloid Neoplasms
1. Clonal haemotopoiesis
2. Myeloproliferative neoplasms
a. Chronic myeloid leukaemia
b. Polycythaemia vera
c. Essential thrombocythaemia
d. Primary myelofibrosis (PMF)
- Prefibrotic/early PMF
- Overt fibrotic PMF
e. Chronic neutrophilic leukaemia
f. Chronic eosinophilic leukaemia
g. Juvenile myelomonocytic leukaemia
h. Myeloproliferative neoplasm, unclassifiable
3. Mastocytosis
a. Cutaneous mastocytosis
- Urticaria pigmentosa/Maculopapular cutaneous mastocytosis
o Monomorphic
o Polymorphic
- Diffuse cutaneous mastocytosis
- Cutaneous mastocytoma
o Isolated mastocytoma
o Multilocalized mastocytoma
b. Systemic mastocytosis
- Bone marrow mastocytosis
- Indolent systemic mastocytosis
- Smoldering systemic mastocytosis
- Aggressive systemic mastocytosis
- Mast cell leukaemia
c. Mast cell sarcoma
4. Myelodysplastic neoplasms (MDS)
a. MDS with defining genetic abnormalities
- MDS with low blasts and isolated 5q deletion (MDS-5q)
- MDS with low blasts and SF3B1 mutationa (MDS-SF3B1)a
- MDS with biallelic TP53 inactivation (MDS-biTP53)
b. MDS, morphologically defined
- MDS with low blasts (MDS-LB)
- MDS, hypoplasticb (MDS-h)
- MDS with increased blasts (MDS-IB)
o MDS-IB1
o MDS-IB2
o MDS with fibrosis (MDS-f)
c. Childhood myelodysplastic syndrome

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 WHO Classification 5th Edition

- Childhood MDS with low blasts

o Hypocellular
o NOS
- Childhood MDS with increased blasts
a
Detection of ≥15% ring sideroblasts may substitute for SF3B1 mutation. Acceptable related
terminology: MDS with low blasts and ring sideroblasts.
b
By definition, ≤25% bone marrow cellularity, age adjusted.

5. Myelodysplastic/myeloproliferative neoplasms
a. Chronic myelomonocytic leukaemia
b. Myelodysplastic/myeloproliferative neoplasm with neutrophilia
c. Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis
d. Myelodysplastic/myeloproliferative diseases, NOS
6. Acute myeloid leukaemia (AML) & related neoplasms
e. AML with defining genetic abnormalities
- Acute promyelocytic leukaemia with PML::RARA fusion
- AML with RUNX1::RUNX1T1 fusion
- AML with CBFB::MYH11 fusion
- AML with DEK::NUP214 fusion
- AML RBM15::MRTFA fusion
- AML with BCR::ABL1 fusion
- AML with KMT2A rearrangement
- AML with MECOM rearrangement
- AML with NUP98 rearrangement
- AML with NPM1 mutation
- AML with CEBPA mutation
- AML, myelodysplasia-related
- AML with other defined genetic alterations
f. AML, defined by differentiation
- AML with minimal differentiation
- AML without maturation
- AML with maturation
- Acute myelomonocytic leukaemia
- Acute monocytic leukaemia
- Acute erythroid leukaemia
- Acute megakaryoblastic leukaemia
- Acute basophilic leukaemia
g. Myeloid sarcoma
h. Myeloid proliferations related to Down syndrome
- Transient abnormal myelopoiesis associated with Down syndrome
- Myeloid leukaemia associated with Down syndrome
7. Secondary myeloid neoplasms
a. Myeloid neoplasms post cytotoxic therapy
b. Myeloid neoplasms with germ line predisposition

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 WHO Classification 5th Edition

- Myeloid neoplasms with germ line predisposition without a pre-existing disorder or

organ dysfunction
o Germline CEBPA pathogenic/likely pathogenic (P/LP) variant (CEBPA-associated
familial AML)
o Germline DDX41 P/LP varianta
o Germline TP53 P/LP varianta (Li-Fraumeni syndrome)
- Myeloid neoplasms with germ line predisposition and pre-existing platelet disorders
o Germline RUNX1 P/LP varianta (familial platelet disorder with associated myeloid
malignancy, FPD-MM)
o Germline ANKRD26 P/LP varianta (Thrombocytopenia 2)
o Germline ETV6 P/LP varianta (Thrombocytopenia 5)
- Myeloid neoplasms with germ line predisposition and potential organ dysfunction
o Germline GATA2 P/LP variant (GATA2-deficiency)
o Bone marrow failure syndromes
▪ Severe congenital neutropenia (SCN)
▪ Shwachman-Diamond syndrome (SDS)
▪ Fanconi anaemia (FA)
o Telomere biology disorders
o RASopathies (Neurofibromatosis type 1, CBL syndrome, Noonan syndrome or
Noonan syndrome-like disordersa,b)
o Down syndromea,b
o Germline SAMD9 P/LP variant (MIRAGE Syndrome)
o Germline SAMD9L P/LP variant (SAMD9L-related Ataxia Pancytopenia
Syndrome)c
o Biallelic germline BLM P/LP variant (Bloom syndrome)
a
Lymphoid neoplasms can also occur.
b
See respective sections.
c
Ataxia is not always present
8. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions
a. PDGFRA rearrangement
b. PDGFRB rearrangement
c. FGFR1 rearrangement
d. JAK2 rearrangement
e. FLT3 rearrangement
f. ETV6::ABL1 fusion
g. Other defined tyrosine kinase fusions:
ETV6::FGFR2; ETV6::LYN; ETV6::NTRK3; RANBP2::ALK; BCR::RET; FGFR1OP::RET
9. Acute leukaemias of mixed or ambiguous lineage
a. Acute leukaemia of ambiguous lineage with defining genetic abnormalities
- Mixed phenotype acute leukaemia with BCR::ABL1 fusion
- Mixed phenotype acute leukaemia with KMT2A rearrangement
- Acute leukaemia of ambiguous lineage with other defined genetic alterations
o Mixed-phenotype acute leukaemia with ZNF384 rearrangement
o Acute leukaemia of ambiguous lineage with BCL11B rearrangement
b. Acute leukaemia of ambiguous lineage, immunophenotypically defined

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 WHO Classification 5th Edition

- Mixed phenotype acute leukaemia, B/myeloid, NOS

- Mixed phenotype acute leukaemia, T/myeloid, NOS
- Mixed-phenotype acute leukaemia, rare types
- Acute leukaemia of ambiguous lineage, not otherwise specified
- Acute undifferentiated leukaemia
10. Histiocytic/dendritic cell neoplasms
a. Plasmacytoid dendritic cell neoplasms
- Mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm
- Blastic plasmacytoid dendritic cell neoplasm
b. Langerhans cell and other dendritic cell neoplasms
- Langerhans cell neoplasms
o Langerhans cell histiocytosis
o Langerhans cell sarcoma
- Other dendritic cell neoplasms
o Indeterminate dendritic cell tumour
o Interdigitating dendritic cell sarcoma
c. Histiocytic neoplasms
- Juvenile xanthogranuloma
- Erdheim-Chester disease
- Rosai-Dorfman disease
- ALK-positive histiocytosis
- Histiocytic sarcoma

Lymphoid Neoplasms
B-cell lymphoid proliferations and lymphomas
1. Tumour-like lesions with B-cell predominance
a. Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma
b. IgG4-related disease
c. Unicentric Castleman disease
d. Idiopathic multicentric Castleman disease
e. KSHV/HHY8-associated multicentric Castleman disease
2. Precursor B-cell lneoplasms
a. B-cell lymphoblastic leukaemias/lymphomas
- B lymphoblastic leukaemia/lymphoma, NOS
- B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy
- B-lymphoblastic leukaemia/lymphoma with hypodiploidy
- B-lymphoblastic leukaemia/lymphoma with iAMP21
- B-lymphoblastic leukaemia/lymphoma with BCR::ABL1 fusion
- B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like features
- B-lymphoblastic mphoblastic leukaemia/lymphoma with KMT2A rearrangement
- B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusion
- B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1-like features
- B-lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusion
- B-lymphoblastic leukaemia/lymphoma with IGH::IL3 fusion

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 WHO Classification 5th Edition

- B-lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion

- B-lymphoblastic leukaemia/lymphoma with other defined genetic abnormalities
3. Mature B-cell neoplasms
n. Pre-neoplastic and neoplastic small lymphocytic proliferations
- Monoclonal B-cell lymphocytosis (MBL)
o Low-count MBL or clonal B-cell expansion
o CLL/SLL-type MBL
o Non-CLL/SLL-type MBL
- Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL)
o. Splenic B-cell lymphomas and leukaemias
- Hairy cell leukaemia
- Splenic marginal zone lymphoma
- Splenic diffuse red pulp small B-cell lymphoma
- Splenic B-cell lymphoma/leukaemia with prominent nucleoli
p. Lymphoplasmacytic lymphoma
- Lymphoplasmacytic lymphoma
q. Marginal zone lymphoma
- Extranodal marginal zone B lymphoma of mucosa-associated lymphoid tissue (MALT
lymphoma)
- Primary cutaneous marginal zone lymphoma
- Nodal marginal zone lymphoma
- Paediatric marginal zone lymphoma
r. Follicular lymphoma
- In situ follicular B-cell neoplasm
- Follicular lymphoma
- Testicular follicular lymphoma
- Paediatric-type follicular lymphoma
- Duodenal-type follicular lymphoma
s. Cutaneous follicle centre lymphoma
- Primary cutaneous follicle centre lymphoma
t. Mantle cell lymphoma
- In situ mantle cell neoplasia
- Mantle cell lymphoma
- Leukaemic non-nodal mantle cell lymphoma
u. Transformations of indolent B-cell lymphomas
- Transformations of indolent B-cell lymphomas
v. Large B-cell lymphomas
- Diffuse large B-cell lymphoma (DLBCL), NOS
o Germinal center B-cell type
o Activated B-cell type
- T cell/histiocyte-rich large B-cell lymphoma
- ALK positive large B-cell lymphoma
- Large B-cell with IRF4 rearrangement
- High grade B-cell lymphoma with 11q aberrations
- Lymphomatoid granulomatosis

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 WHO Classification 5th Edition

- EBV-positive DLBCL
- DLBCL associated with chronic inflammation
- Fibrin-associated diffuse large B-cell lymphoma
- Fluid overload-associated large B-cell lymphoma
- Plasmablastic lymphoma
- Primary large B-cell lymphoma of immune-privileged sites
- Primary cutaneous DLBCL, leg type
- Intravascular large B cell lymphoma
- Primary mediastinal (thymic) large B-cell lymphoma
- Mediastinal grey zone lymphoma
- High-grade B-cell lymphoma, NOS
w. Burkitt lymphoma
- Burkitt lymphoma
x. KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas
- Primary effusion lymphoma
- KSHV/HHV8-positive DLBCL
- HHV8-positive germinotropic lymphoproliferative disorder
y. 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
z. Hodgkin lymphoma
- Classical Hodgkin lymphoma
o Nodular sclerosis classical Hodgkin lymphoma
o Mixed cellularity classical Hodgkin lymphoma
o Lymphocyte-rich classical Hodgkin lymphoma
o Lymphocyte-depleted classical Hodgkin lymphoma
- Nodular lymphocyte predominant Hodgkin lymphoma
4. Plasma cell neoplasms and other diseases with paraproteins
e. Monoclonal gammopathies
- Cold agglutinin disease
- IgM monoclonal gammopathy of undetermined significance (MGUS)
- Non-IgM MGUS
- Monoclonal gammopathy of renal significance
f. Diseases with monoclonal immunoglobulin deposition
- Immunoglobulin-related (AL) amyloidosis
- Monoclonal immunoglobulin deposition disease
g. Heavy chain disease
- Mu heavy chain disease
- Gamma heavy chain disease
- Alpha heavy chain disease
h. Plasma cell neoplasms

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 WHO Classification 5th Edition

- Plasmacytoma
o Solitary plasmacytoma of bone
o Extraosseous plasmacytoma
- Plasma cell myeloma
- Plasma cell neoplasms with associated paraneoplastic syndrome
o POEMS syndrome
o TEMPI syndrome
o AESOP syndrome

T-cell and NK-cell lymphoid proliferations and lymphomas

1. Tumour-like lesions with T-cell predominance

a. Kikuchi-Fujimoto disease
b. Indolent T-lymphoblastic proliferation
c. Autoimmune lymphoproliferative syndrome
2. Precursor T-cell neoplasms
a. T-lymphoblastic leukaemia/lymphoma
- T-lymphoblastic leukaemia / lymphoma, NOS T-lymphoblastic leukaemia/lymphoma
- Early T-precursor lymphoblastic leukaemia / lymphoma
3. Mature T- & NK-cell neoplasms
a. Mature T-cell & NK-cell leukaemia
- T-prolymphocytic leukaemia
- T-large granular lymphocytic leukaemia
- NK-large granular lymphocytic leukaemia
- Adult T-cell leukaemia/lymphoma
- Sézary syndrome
- Aggressive NK-cell leukaemia
b. Primary cutaneous T-cell lymphomas
- Primary cutaneous CD4 positive small/medium T-cell lymphoproliferative disorder
- Primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder
- Mycosis fungoides
- Primary cutaneous CD30 positive T-cell lymphoproliferative disorders: Lymphomatoid
papulosis
- Primary cutaneous CD30 positive T-cell lymphoproliferative disorders: 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 (PTCL), NOS
c. Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
- Indolent T-cell lymphoma of the GIT
- Indolent NK-cell lymphoproliferative disorder of the GIT
- Enteropathy-associated T-cell lymphoma
- Monomorphic epitheliotropic intestinal T-cell lymphoma
- Intestinal T-cell lymphoma, NOS

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 WHO Classification 5th Edition

d. Hepatosplenic T-cell lymphoma

- Hepatosplenic T-cell lymphoma
e. Anaplastic large-cell lymphoma
- ALK-positive anaplastic large-cell lymphoma
- ALK-negative anaplastic large-cell lymphoma
f. Nodal T-follicular helper (TFH) cell lymphoma
- Nodal TFH cell lymphoma, angioimmunoblastic-type
- Nodal TFH cell lymphoma, follicular-type
- Nodal TFH cell lymphoma, NOS
g. Other PTCL
- PTCL, NOS
h. EBV-positive NK/T-cell lymphomas
- EBV-positive nodal T- and NK-cell lymphoma
- Extranodal NK/T-cell lymphoma
i. EBV-positive T- and NK-cell lymphoid proliferations and lymphomas of childhood
- Severe mosquito bite allergy
- Hydroa vacciniforme-like lymphoproliferative disorder
- Systemic chronic active EBV disease
- Systemic EBV+ T-cell lymphoproliferative disease of childhood

Stroma-derived neoplasms of lymphoid tissues

1. Mesenchymal dendritic cell neoplasms

- Follicular dendritic cell sarcoma (Same)
- EBV-positive inflammatory follicular dendritic cell sarcoma Inflammatory pseudotumour-like
follicular/fibroblastic dendritic cell sarcoma
- Fibroblastic reticular cell tumour (Same)
2. Myofibroblastic tumour
- Intranodal palisaded myofibroblastoma Not previously included
3. Spleen-specific vascular-stromal tumours
- Splenic vascular-stromal tumours
- Littoral cell angioma Not previously included
Splenic hamartoma Not previously included
Sclerosing angiomatoid nodular transformation of spleen

References

1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization
Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia.
2022;36(7):1720-48. doi: 10.1038/s41375-022-01620-2
2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification
of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia.
2022;36(7):1703-19. doi: 10.1038/s41375-022-01613-1

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