|Year : 2010 | Volume
| Issue : 3 | Page : 391-394
|Two steps forward, one step back: 4th WHO classification of myeloid neoplasms (2008)
Rahul Bhargava1, Bakul I Dalal2
1 From the Division of Hematology, Vancouver General Hospital, Vancouver, BC, Canada
2 From the Division of Hematopathology, Vancouver General Hospital, Vancouver, BC, Canada
Click here for correspondence address and email
|Date of Web Publication||22-Oct-2010|
|How to cite this article:|
Bhargava R, Dalal BI. Two steps forward, one step back: 4th WHO classification of myeloid neoplasms (2008). Indian J Pathol Microbiol 2010;53:391-4
|How to cite this URL:|
Bhargava R, Dalal BI. Two steps forward, one step back: 4th WHO classification of myeloid neoplasms (2008). Indian J Pathol Microbiol [serial online] 2010 [cited 2021 Aug 1];53:391-4. Available from: https://www.ijpmonline.org/text.asp?2010/53/3/391/68240
Classification is the language of medicine; diseases must be described and classified before they can be studied and treated uniformly. Classification is an effort so that everyone can speak the same language.
Myeloid neoplasms include acute and chronic leukemias, as well as chronic myeloproliferative and myelodysplastic disorders. Clearly, the myeloid neoplasms are a diverse group. Initial attempts at classification were based on the clinical features, morphology and cytochemistry, and led to the French-American-British (FAB) classification. , FAB classification was extremely useful in guiding the therapy and in preliminary understanding of their biology. Addition of another parameter, flow cytometry, helped refine the FAB classification, specifically to identify the megakaryoblastic subtype and minimally differentiated acute myeloid leukemia (AML).  It was soon realized that the categories defined by the FAB classification were clinically and biologically heterogeneous. In 1997, a group of pundits from around the world gathered in Airlie, Virginia, USA, to add yet another discriminator, cytogenetics, to the mix; thus the 3 rd WHO Classification of hematopoietic neoplasm was born in 2001.  Since 2001, the discovery of many molecular abnormalities in myeloid neoplasms fundamentally changed our understanding of their biology and management, and yet another revision was necessary. The 4 th WHO classification, published in 2008, looks radically different from its predecessor. It includes new entities and groups recognized by molecular genetic abnormalities and also a number of new provisional entities that have been characterized in the past few years. 
In this review, we have highlighted the salient features and major changes in diagnosis and classification of myeloid neoplasms. In addition, we have also discussed a few shortcomings, some quirks, occasional issues with this scheme and reviewed recent literature raising these issues.
Laboratory Issues in Applying the 4 th WHO Classification
The following are the laboratory issues in applying the 4 th WHO classification:
1. Specimen requirements
- Blood and marrow specimens should be collected before starting therapy
- Bone marrow (BM) biopsy from every case, minimum 1.5 cm long and at right angle to the cortex
- Marrow (not blood) for cytogenetic, molecular genetic, flow cytometric examination, and for cryopreservation
2. Assessment of blasts in blood and bone marrow (aspirate and biopsy)
- Microscopic blast differential count to be done, not flow cytometric; 200 cells in blood and 500 cells in marrow
- Count as blasts - myeloblasts, monoblasts, promonocytes, megakaryoblasts (but not dysplastic megakaryocytes) and abnormal promyelocytes. Proerythroblasts are not counted as blasts except in rare instances of pure acute erythroleukemia
- If the aspirate is poor and/ or marrow fibrosis is present, immunohistochemistry (IHC) on biopsy sections for CD34 may be informative if blasts are CD34+. Proper decalcification is very important to preserve CD34 antigen.
3. Assessment of blast lineage
- Multiparameter flow cytometry, >3 colors is recommended; panel should be sufficient to determine lineage as well as aberrant antigen profile of neoplastic population
- Cytochemistry, myeloperoxidase or nonspecific esterase helpful in AML, Not otherwise specified (NOS), but it is not essential in all cases
- IHC on biopsy
4. Genetic assessment
- Cytogenetics from BM should be done at initial diagnosis
- Additional studies, e.g., Fluorescent in situ hybridization (FISH), Reverse transcriptase- polymerase chain reaction (RT-PCR) and mutation status, should be done depending on the clinical, laboratory and morphologic information
- Molecular studies for NPM1, CEBPA and FLT3 for CN-AML
- Molecular studies for JAK2 in all BCR-ABL1-negative MPNs
- Molecular analysis for c-KIT, NRAS, PTNP11
- All data should be assimilated into one report that states the WHO diagnosis [Table 1]
What is New? [5,6] / What is Controversial?
AML and related precursor neoplasms
1. AML with recurrent genetic abnormalities
- Rule of 20% blasts needed for diagnosis of acute leukemia does not apply to AML with t(8;21)(q22;q22), inv(16)(p13.1q22) or (16;16)(p13.1;q22); and APL with t(15;17)(q22;q12). However, AML with t(9;11)(p22;q23) or other 11q23 abnormalities, and all other subgroups still require 20% blasts.
- Variant translocations of APL [e.g., t(11;17) or t(5;17)] are recognized separately because they may not have typical APL clinical and morphological features, and some are all-trans retinoic acid (ATRA) resistant.
- AML with 11q23 (MLL) abnormalities is now restricted to t(9;11)(p22;q23) MLLT3-MLL. Other abnormalities should be specified in the diagnosis. Partial tandem duplication of MLL should not be placed in this category.
- Three new categories
- t(6;9)(p23;q34); DEK-NUP214
- inv(3)(q21;q26.2) or t(3;3)(q21;q26.2) RPN1-EVI1
- AML-M7 with t(1;22)(p13;q13); RBM15-MKL1
- Two new provisional entities
- AML with mutated NPM1
- AML with mutated CEBPA
- FLT3-ITD not recognized as a separate category (even though half of the world uses this as a strong prognostic factor). However, FLT3 testing strongly recommended in all cases of cytogenetically normal AML.
2. AML with myelodysplasia-related changes
- Name change "AML with multilineage dysplasia" > changed to "AML with myelodysplasia-related changes"
- Diagnostic criteria defined
- History of MDS or MDS/MPN
- MDS-related cytogenetics
- >50% of cells in ≥2 cell lines, dysplastic
- Do we need this category? AML-MLD  (as per 2001 WHO criteria) morphological dysplasias were not significant in a large German study of 1,332 patients with AML.  A subsequent smaller study, using 2008 WHO criteria on a small number of patients, did find significant association. 
3. Therapy-related myeloid neoplasms
- Subcategories "alkylating agent-related" and "topoisomerase II-inhibitor-related" are merged.
4. AML, NOS
- Some cases of acute erythroid leukemia or acute megakaryoblastic leukemia may be reclassified as AML with myelodysplasia-related changes.
- Acute megakaryoblastic leukemia should be placed elsewhere if inv(3)(q21; q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1, or AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1.
- Down syndrome-related cases are excluded from this category.
5. Myeloid proliferations related to Down syndrome
New category added.
6. Blastic plasmacytoid dendritic cell neoplasm
New category added, previously classified as blastic NK-cell lymphoma/leukemia or agranular CD4 / CD56 hematodermic neoplasm; it is derived from a precursor of plasmacytoid dendritic cells.
Acute Leukemia of Ambiguous Lineage
- The criteria for myeloid, T- and B- changed.
- Bilineal and biphenotypic now merged into "mixed-phenotype acute leukemia" (MPAL).
- Cases of BCR-ABL1-positive and MLL-positive acute leukemias may meet the criteria for MPAL.
- In the case of BCR-ABL1-positive disease, CML in blast phase should be excluded.
- Blastic natural killer cell leukemia/lymphoma , - not easily defined; considered a provisional entity; most cases now recognized as blastic plasmacytoid dendritic cell neoplasms - CD4+/ CD56+/ CD36+/ CD123+.
[Table 2],[Table 3],[Table 4]
- MDS-related cytogenetic abnormalities enough to call MDS even if no morphological features.
- Refractory cytopenia with unilineage dysplasia - new category to replace refractory anemia (RA); now includes not only RA but also neutropenia (unilineage dysgranulopoiesis) and refractory thrombocytopenia (unilineage dysmegakaryopoiesis).
- RCMD and RCMD-RS merged.
- Blasts in blood are important!  Patients with 2% to 4% blasts in the blood and less than 5% blasts in the bone marrow should be diagnosed as having RAEB-1 if other clinical and laboratory findings of MDS are present.
- New provisional entity, refractory cytopenia of childhood (RCC), has been added to include children with cytopenia(s) with >2% blasts in blood and >5% in the bone marrow and evidence of dysplasia in 2 or more lineages. For children with 2% to 19% blasts in the blood and/ or 5% to 19% in the bone marrow, the MDS subclassification should be done using the same criteria used for adults.
- Neglect of hypoplastic cases.  Hypoplastic MDS and AML have better prognosis and should be clearly recognized as such. Also, hypoplastic MDS should be differentiated from aplastic anemia which does not progress to acute leukemia, and is treated by Antithymocyte Globulin rather than chemotherapy.
Myeloproliferative Neoplasms (MPN)
[Table 5],[Table 6],[Table 7]
- Name change - MPD >MPN
- Diagnostic algorithms for Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) changed to include JAK2 V617F and other genetic abnormalities and other clinical, lab and histologic  features.
- The platelet count threshold for ET has been reduced from platelet count of 600x 109 to 450x10 9 . Recent literature validates this change. The ET patients with platelet count of >600 x 10 9 /L had the same clinical course and complications as those with platelet count of 450-600 x 10 9 /L. 
- Some (not all) cases of chronic eosinophilic leukemia (CEL) now in the new group.
- Systemic mastocytosis back in this group.
|Table 6: Myeloid and lymphoid neoplasms/w eosinophilia and Abn of PDGFRA, PDGFRB, FGFR1|
Click here to view
- Some cases of CMML with eosinophilia now in the new group.
- Name change - atypical CML > atypical CML, BCR-ABL1-negative.
- RARS-T defined in more detail, still a "provisional entity." The criteria have been modified to include refractory anemia, dyserythropoiesis in the bone marrow, with ring sideroblasts accounting for 15% or more of erythroid precursors and megakaryocytes with features resembling those in PMF or ET; the platelet threshold is lowered to 450΄10 9 /L. Recent suggestion RARS-T that this disorder is an MPN and ringed sideroblasts is a nonspecific finding. 
| Conclusion|| |
The 4 th edition of WHO classification is a giant leap, where modern technology has contributed immensely in identifying the new disease subsets, which have great prognostic values. Already, in the few months since the publication of the 4 th edition, new information is accumulating that will eventually lead to our ability to recognize new diseases and change our criteria for the diseases already described. We in India should try to continually review, update and test this classification and try to make contributions to it.
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Bakul I Dalal
Vancouver General Hospital, Vancouver, BC V5Z 4E3
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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