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

1. The 5th edition of the World Health Organization Classification of
Haematolymphoid Tumours:
Myeloid and Histiocytic/Dendritic Neoplasms
Dr. Seena Tresa Samuel
Pathologist

2. Clonal haematopoiesis (CH)
• Presence of a population of cells with selective growth advantage
• Derived from a mutated multipotent stem/progenitor cell
• Absence of unexplained cytopenias, haematological cancers, or clonal disorders.
• Associated with increased overall mortality, cardiovascular diseases, and
myeloid malignancies

3. Clonal haematopoiesis of indeterminate potential (CHIP)
• CH harbouring somatic mutations of myeloid malignancy-associated genes
detected in the blood or BM at a variant allele fraction (VAF) of ≥ 2% (≥4%
for X-linked gene mutations in males) in individuals without a diagnosed
haematologic disorder or unexplained cytopenia

4. Clonal cytopenia of undetermined significance (CCUS)
• CHIP detected in the presence of one or more persistent cytopenias
• Unexplained by haematologic or non-haematologic conditions
• Do not meet diagnostic criteria for defined myeloid neoplasms.

5. Definition of Cytopenia
• Cytopenia definitions are harmonized for CCUS, MDS, and MDS/MPN
Anaemia- Hb <13g/dL in males and <12 g/dL in females
Leukopenia -Absolute neutrophil count <1.8 ×10⁹/L
Thrombocytopenia -Platelets <150 × 10⁹/L

6. MYELOPROLIFERATIVE NEOPLASMS

7. Chronic myeloid leukaemia
• Incidence of progression to advanced phase disease has decreased with TKI
therapy: - Omitted the Accelerated phase
• CML phases consolidated into chronic and blast phases
• Resistance stemming from ABL1 kinase mutations and/or additional
cytogenetic abnormalities represent key disease attributes

8. • Criteria for Blast Phase include:
(1) ≥20% myeloid blasts in the blood or bone marrow Or
(2) Presence of an extramedullary proliferation of blasts Or
(3) Presence of increased lymphoblasts in peripheral blood or bone marrow.
The optimal cut off for lymphoblasts remain unclear

9. BCR::ABL1-negative myeloproliferative neoplasms
Polycythemia Vera

10. • Diagnostic criteria of PMF and ET remains unchanged.
• PMF, PV and ET can progress to Accelerated phase (10-19% blasts) and Blast
phase (≥20% blasts)
• Driver events: JAK2, CALR, and MPL mutations
• Poorer prognostic risk :EZH2, IDH1, IDH2, SRSF2, U2AF1, and ASXL1 mutations
• Chronic neutrophilic leukaemia: CSF3R mutations are detected in >60% of cases

11. Chronic eosinophilic leukaemia (NOS Removed)
1. Sustained hypereosinophilia time interval- reduced from 6 months to 4 weeks
2. Both Clonality and abnormal BM morphology required (eg.megakaryocytic or
erythroid dysplasia)
3. Elimination of increased blasts as an alternative to clonality.

12. Juvenile myelomonocytic leukaemia
• Recognized as MPN of early childhood - Categorized under MPN.
• Updates to diagnostic criteria include:
(1) Exclusion of KMT2A rearrangements
(2) Elimination of monosomy 7 as a cytogenetic criterion
(3) Emphasizing diagnostic molecular studies to demonstrate RAS pathway
activation
• somatic mutations involving PTPN11 and germline pathogenic variants
associated with NF-1 -aggressive types
• Germline CBL variants -occasionally spontaneous remission.

13. MASTOCYTOSIS
• CD30 and any KIT mutation - introduced as minor diagnostic criteria of SM
• Bone marrow mastocytosis is a new SM subtype.
(Absence of skin lesions, Basal Serum tryptase below 125 ng/ml and B-findings)
• KIT D816V mutation with VAF ≥ 10% qualifies as a B-finding (burden of disease)

14. MYELODYSPLASTIC NEOPLASMS (MDS)
• Threshold for dysplasia set at 10% for all lineages
• Single lineage and multilineage dysplasia is optional- No. of dysplastic lineages
is dynamic ,represents phenotypic manifestation of clonal evolution
• MDS, Unclassifiable has been removed due to incorporation of CCUS
• MDS with low blasts (MDS-LB) and MDS with increased blasts (MDS-IB) – cut
offs retained.

16. MDS with defining genetic abnormalities
• MDS with low blasts and isolated 5q deletion – (Blasts <5% BM and <2% PB)
• With/without SF3B1 or a TP53 mutation(not multi-hit)
• No monosomy 7or 7q deletion
• MDS with low blasts and SF3B1 mutation (MDS-SF3B1)
• Includes over 90% of MDS with ≥5% ring sideroblasts
• MDS with low blasts and ring sideroblasts retained - used for cases with
wild-type SF3B1 and ≥15% ring sideroblasts.
• MDS with biallelic TP53 inactivation(MDS-biTP53)- <20% blasts in BM & PB
• Multihit mutational status with no residual wild type p53 protein
• AML equivalent for therapeutic considerations

17. MDS, morphologically defined
• MDS with low blasts (MDS-LB) - <5% BM and <2% PB
• MDS, hypoplastic (MDS-h)-(≤25% bone marrow cellularity, age adjusted)
• MDS with increased blasts (MDS-IB)
MDS-IB1 : 5–9% BM or 2–4% PB
MDS-IB2 : 10-19% BM or 5–19%PB or Auer rods
MDS with fibrosis (MDS-f): 5–19% BM; 2–19% PB

18. Practical challenges in blast counts
(1) Any blast-based cutoff is arbitrary and cannot reflect the biologic continuity
naturally inherent in myeloid pathogenic mechanisms
(2) Blast enumeration is subjective
(3) No gold standard for blast enumeration exists

19. Consensus
• Eliminating blast cutoffs for most AML types with defining genetic alterations
• Retaining a 20% blast cutoff to delineate MDS from AML.
• MDS-IB2 may be regarded as AML-equivalent for therapeutic considerations

20. Childhood myelodysplastic neoplasms(<18years)
• JMML, myeloid proliferations associated with Down syndrome, and MDS
post cytotoxic therapy are excluded .
• Childhood MDS with low blasts replaces the term “refractory cytopenia of
childhood (RCC)”.

21. • Exclusion of non-neoplastic causes of cytopenia (infections, nutritional
deficiencies, metabolic diseases, bone marrow failure syndromes etc.)remains an
essential diagnostic prerequisite for childhood MDS with low blasts.
• Monosomy 7, 7q deletion, complex karyotype - increased risk of AML
• Normal karyotype or trisomy 8 - indolent course

22. MYELODYSPLASTIC / MYELOPROLIFERATIVE NEOPLASMS
Revised 4th edition
5th edition

23. Chronic myelomonocytic leukaemia

24. • CMML Subtypes:
a. Myelodysplastic CMML (MD-CMML) (WBC < 13 × 109/L)
b. Myeloproliferative CMML (MP-CMML) (WBC ≥ 13 × 109/L).
• CMML-0 (<2%blasts in PB & <5% blasts in BM) has been eliminated
• CMML-1: <5% in peripheral blood and <10% in bone marrow
• CMML-2: 5–19% in peripheral blood and 10-19% in bone marrow

25. ACUTE MYELOID LEUKEMIA
• AML with defining genetic abnormalities
• AML defined by differentiation.( Eliminates the term AML, NOS )
• AML with other defined genetic alterations (emerging entities)
• Elimination of the 20% blast requirement - AML types with defining genetic
abnormalities
AML with BCR::ABL1 fusion & AML with CEBPA mutation- requires 20% blasts
• AML with RUNX1 mutation is not recognized as a distinct AML type –
Lack specificity, overlap with other defining molecular features

26. Acute myeloid leukemia with defining genetic abnormalities
• APML with PML::RARA fusion
• AML with RUNX1::RUNX1T1 fusion
• AML with CBFB::MYH11 fusion
• AML with DEK::NUP214 fusion
• AML with RBM15::MRTFA fusion
• AML with BCR::ABL1 fusion
• AML with KMT2A rearrangement (replaces “AML with t(9;11); KMT2A-MLLT3”.)
• AML with MECOM rearrangement
• AML with NUP98 rearrangement
• AML with NPM1 mutation
• AML with CEBPA mutation (both biallellic CEBPA &single mutations)
• Acute myeloid leukaemia, myelodysplasia-related
• AML with other defined genetic alterations (rare emerging)

27. AML, myelodysplasia-related (AML-MR).
• Formerly - AML with myelodysplasia-
related changes.
1. Removal of morphology alone as a
diagnostic premise
2. Update of defining cytogenetic criteria
3. Introduction of defining somatic
mutation in 8 genes
1 or more cytogenetic / molecular
abnormalities and/or
history of MDS or MDS/MPN

28. AML defined by differentiation
• Lack defining genetic abnormalities.
• Acute erythroid leukemia: high prevalence of biallelic TP53 alterations.

29. Myeloid sarcoma
• Tissue-based manifestation of AML or transformed MDS, MDS/MPN, or MPN
• De novo cases should be investigated comprehensively including cytogenetic
and molecular studies

30. SECONDARY MYELOID NEOPLASMS
1. Myeloid neoplasms post cytotoxic therapy (MN-pCT)
• Fulfilment of criteria for a myeloid neoplasm (AML,MDS,MDS/MPN)
• Documented history of chemotherapy treatment Or
• Large-field radiation therapy for an unrelated neoplasm
• Exposure to PARP1 inhibitors
• Methotrexate has been excluded
• Usually associated with TP53 mutation (multi-hit)
• Type of myeloid neoplasm +appendix “post cytotoxic therapy”
e.g. CMML post cytotoxic therapy.

31. 2. Myeloid neoplasms associated with germline predisposition
• Arise in individuals with genetic
diseases
• Myeloid neoplasms include AML,
MDS, MPN, and MDS/MPN

32. MYELOID/LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND
TYROSINE KINASE GENE FUSIONS
• Driven by rearrangements of tyrosine kinase genes
• BCR::ABL1-negative diseases
• MPN, MDS, MDS/MPN, AML, MPAL, B / T ALL
• FGFR1, JAK2, FLT3 rearrangement & ETV6::ABL1 fusion – Variable sensitivity to TKI
5th edition

33. ACUTE LEUKAEMIAS OF MIXED OR AMBIGUOUS LINEAGE
1. Acute leukaemia of ambiguous lineage with defining genetic alterations
• Mixed-phenotype acute leukaemia with BCR::ABL1 fusion
• Mixed-phenotype acute leukaemia with KMT2A rearrangement
• MPAL with ZNF384 rearrangement ( B/myeloid immunophenotype- pediatric)
• ALAL with BCL11B rearrangement (AUL, T/myeloid MPAL)

34. 2. Acute leukaemia of ambiguous lineage, immunophenotypically defined
• Mixed-phenotype acute leukaemia, B/myeloid
• Mixed-phenotype acute leukaemia, T/myeloid
• Mixed-phenotype acute leukaemia, rare types
• Acute leukaemia of ambiguous lineage, not otherwise specified
• Acute undifferentiated leukaemia

35. Lineage assignment criteria for MPAL are refined
Commitment to a lineage correlates with the intensity and/or pattern of expression
seen on the similar normal population

36. HISTIOCYTIC/DENDRITIC CELL NEOPLASMS
1. Included Mature plasmacytoid dendritic cell proliferation
Clonal plasmacytoid dendritic cell disease
Seen in association with myeloproliferative CMML and AML
2. Rosai-Dorfman disease (RDD) and ALK-positive histiocytosis included.
3. Follicular dendritic cell sarcoma and fibroblastic reticular cell tumor removed from
this category and renamed as “stroma-derived neoplasms of lymphoid tissues”

37. Revised 4th edition
5th edition
Mutations of MAPK
pathway

38. ALK-positive histiocytosis
• Presence of ALK gene translocation (most commonly KIF5B::ALK)
• Response to ALK inhibitor therapy
• Multisystem systemic form occurs in infants- resolves slowly, spontaneously or
with chemotherapy.
• Multisystem /Unisystem occur in other age group
• Morphology overlaps with Juvenile xanthogranuloma and rarely RDD.
• ALK immunostaining recommended for histiocytic proliferations

39. Summary..
• Clonal hematopoiesis : a category of precursor myeloid disease state
• CML phases consolidated into chronic and blast phases
• Diagnostic criteria of CEL are updated
• JMML is categorized under myeloproliferative neoplasms.
• CD30 & any KIT mutation introduced as minor diagnostic criteria of Mastocytosis

40. • Hypoplastic MDS (MDS-h) is recognized as a distinct disease type.
• New terms: MDS with low blasts and MDS with increased blasts
• Terminology of childhood MDS types is updated
• CMML – cutoff for absolute monocytosis (≥0.5 × 109/ L) , eliminated CMML-0.
• Atypical chronic myeloid leukaemia renamed MDS/MPN with neutrophilia.

41. • AML with defining genetic abnormalities & AML defined by differentiation.
• AML with defining genetic abnormalities - <20% blasts.
• Exposure to PARP1 inhibitors is added as a qualifying criterion for MNpCT.
• Lineage assignment criteria for MPAL are refined to emphasize principles of
intensity and pattern.
• ALK-positive histiocytosis is introduced as a new entity.

42. THANK YOU