|Laboratoire d' Hématologie, Hôpital Necker-Enfants Malades, Paris, France|
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|ICD-Topo||C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS|
|ICD-Morpho||9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS|
|ICD-Morpho||9920/3 Therapy-related myeloid neoplasms|
|Note|| Basis of classification in conformity with WHO recommandations.
The classification of acute myeloid leukemia (AML) and myelodysplasic syndromes (MDS) includes clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular biology). The separation of homogeneous classes allows us to distinguish pronostic parameters and to identify groups of patients sensitive to drugs or to specific treatment. Recurrent cytogenetic abnormalities are strong prognostic indicators in AML and MDS. Molecular studies of structural chromosomal changes have enabled the cloning of genes located at chromosomal breakpoints and have helped to characterize the proteins involved in leukemogenesis. Morphologic studies remain important because of a strong correlation with cytogenetic and molecular abnormalities.
The clinico-biological classification of acute myeloid leukemia (AML) should include morphological, cytochemical, immunophenotypic, cytogenetic and molecular characterization of the leukemia blasts. The identification of homogeneous categories would allow the development and refinement of treatment strategies.
Rationale for a new classification approach
2. Clinics and Pathology
|Disease||First group WHO: AML with "recurrent cytogenetic translocations"|
|Note|| Although the term "de novo" is not fully appropriate (see below "secondary AML"), this category of patients is usually referred as such in the literature since MDS or chemo/radiotherapy does not usually precede them either. The most commonly identified abnormalities are reciprocal translocations: t(8;21), inv(16) or t(16;16), t(15;17), t(11;17), t(9;11), t(6;9), t(1;22) and t(8;16). Molecular studies have shown that these structural chromosome rearrangements create a fusion gene encoding a chimeric protein. Most can be detected by RT-PCR including complex and cryptic cytogenetic variants. The altered expression and/or structure of cellular gene products leads to functional activation that may contribute to the initiation or progression of leukemogenesis.|
The most frequent anomalies are : t(8;21)(q22;q22) - inv/del16( p13q22)/del(16)(q22)/t(16;16)(p13q22) - t(15;17)(q22;q21) - t(11;17)(q23;q21) - 11q23
|Cytogenetics|| t(8;21)(q22;q22) |
DEFINITION: The translocation t(8;21)(q22;q22) is one of the most common structural aberration in acute myeloid leukemia and is found in 5-12% of AML and in one-third of karyotypically abnormal M2 cases according to the French-American-British (FAB) classification.
DEFINITION: Patients with inv(16)(p13q22) usually correspond to the subclass of AML M4, with a specific abnormal eosinophil component and is considered as a distinct entity in correlation with these specific chromosomal abnormalities. These cases of AML M4 are referred as AML M4EO.
DEFINITION: t(15;17)(q22;q21) is associated consistently with M3 AML. This chromosomal abnormality first appeared to be confined to the characteristic or morphologically typical M3 AML or "hypergranular promyelocytic leukemia", defined by bone marrow replacement with highly granulated blast cells, with occasional pseudo Pelger-Huet cells
DEFINITION: Several AML cases with translocation t(11;17)(q23;q21), in which the promyelocytic leukemia zinc finger ( PLZF) gene is translocated to RARalphagene on 17q21 have been reported. This finding that the RARalpha gene is involved in both t(15;17) and t(11;17) suggests the importance of the modified RARalpha in AML.
DEFINITION: Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23.
|Disease||Second group WHO: mAML : Multilineage AML|
|Note||DEFINITION: This category is defined by the presence of multilineage dysplasia on cytological analysis. In contrast to the patients with "recurrent translocation", "multilineage AML" by definition involve all myeloid cell lineages. This category of AML occurs mainly in elderly patients and is rare in children. Translocations typical of "de novo AML" in young patients are not found in "multilineage AML". Dysplasia may be analyzed according to standard criteria (presence in >50% of each cell category). Granulocytic dysplasia (DysG) may be defined as polymorphonuclear neutrophils (PMN) with agranular or with hyposegmented nuclei (pseudo Pelger-Huet anomaly). Dysplastic features of erythroblastic precursors define Erythroid dysplasia (DysE): (megaloblastic or macroblastic aspects, karyorexis, nuclear fragments or multinuclearity). Megakaryocytic dysplasia (DysM) may be diagnosed when micromegakaryocytes, large megakaryocytes with monolobed or with multiple separated nuclei are found. A special mention has to be made of the high frequency of dysmegakaryopoiesis and the utmost importance of clearly separating abnormal megakaryocytic cells with normal ploidy and non lobed ("monolobed") nuclei from hypoploid ("micromegakaryocytes") megakaryocytes and from megakaryocytes with multiple separated nuclei.|
|Cytogenetics||KARYOTYPIC/MOLECULAR ANALYSIS: In this group of patients chromosomes abnormalities include gain or loss of major segments of chromosomes: -5, -7/del(7q), +8, +9, +11, del(11q), del(12p), del(17p), -18, +19, del(20q), +21 and less often specific translocations t(2;11), t(1;7)(q10;p10) and translocations involving 3q21 and 3q26.|
|Disease||Third group WHO: "Secondary AML"|
|Note|| DEFINITION The term "secondary" AML has been utilized to encompass several different situations.|
|Disease||Fourth group WHO: Morpholocical and Immunophenotyping classification|
|Note|| DEFINITION: A morphological and immunophenotypic classification remains necessary for the other situations which do not fit with the two preceding main categories, respectively: "recurrent translocations AML" (so-called "de novo") and "multilineage AML".|
Morphologically, the diagnosis of AML is based on the cytological aspect of the blast cells and the maturation of the different cell lineages in bone marrow aspirate, in addition to quantitative parameters obtained from the peripheral blood. Blood films, although essential, are not considered sufficient for diagnosis. The major criteria required for sub-classification are based on bone marrow aspirates. This explains the care required in difficult cases, in which the bone marrow aspirate is hypocellular. In these cases, as well as those with myelofibrosis, precise diagnosis needs the additional information of histological examination of a bone marrow biopsy. When the bone marrow is hypercellular or normocellular and easy to aspirate, bone marrow biopsy is usually not essential and cytological examination of smears is sufficient. With some reservations the sub-classification criteria can also be used for the material from patients with relapsing acute leukemia.
MORPHOLOGICAL CATEGORIES. The categories of this fourth group reflect the previous FAB classification with eight main types of AML (from M0 to M7 AML) and one additonal category for the so-called "biphenotypic AL". AML M1 and M2 show predominantly granulocytic (neutrophil) differentiation. Very specific hypergranular cells characterize M3 AML. AML M4 and M5 both show monocytic differentiation, predominantly monocytic for M5, and mixed monocytic-granulocytic for M4. Predominantly erythroblastic and megakaryoblastic differentiation are characteristic of AML M6 and M7 AML respectively; the myeloid nature of M0 is defined only on immunological markers (myeloid and no lymphoid markers) in patients lacking morphological or cytochemical criteria for AML. Biphenotypic acute leukemias are defined for patients having both lymphoid and myeloid immunological markers.
|Morphologic, immunologic and cytogenetic (MIC) working classification of the acute myeloid leukaemias. Second MIC Cooperative Study Group.|
|British journal of haematology. 1988 ; 68 (4) : 487-494.|
|Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group.|
|Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C|
|British journal of haematology. 1976 ; 33 (4) : 451-458.|
|World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.|
|Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD|
|Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 ; 17 (12) : 3835-3849.|
|This paper should be referenced as such :|
|Classification of acute myeloid leukemias|
|Atlas Genet Cytogenet Oncol Haematol. 2002;6(3):215-219.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Anomalies/ClassifAMLID1238.html|
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