Classification of acute myeloid leukemias

2002-05-01   Georges Flandrin 

1.Laboratoire d Hématologie, Hôpital Necker-Enfants Malades, Paris, France

Clinics and Pathology


First group WHO: AML with "recurrent cytogenetic translocations"


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 , 
  • A first class of secondary AML include those patients with a longstanding exposure to environmental toxins, including smoking, occupational chemicals such as benzene and related petrochemicals. The importance of detailed occupational history of all patients cannot be overstated. , 
  • The second category corresponds to patients who received prolonged administration of chemotherapy and/or radiotherapy for non-MDS/MPS malignancies (epithelial cancer, malignant lymphomas, myelomas, Hodgkins disease). These AML occur after a latent period of a few years. They may present with myelodysplastic features evolving rapidly to AML. Until recently these were assumed to be exclusively the result of administration of alkylating agents. These AML are frequently associated with acquired chromosomal abnormalities involving 5q, -7/del(7q) and other complex rearrangements, and more rarely with translocations. The morphological presentation and cytogenetic features of these two first types of "secondary" AML (sAML) are somewhat similar to "multilineage AML" (mAML). , 
  • Another situation that has been described more recently is AML developing after the administration of agents that bind to DNA-topoisomerase II. In contrast to the loss of chromosomal material after alkyliting agent exposure, balanced translocations ("de novo" type AML): 11q23, usually t(9;11), or 21q22, t(8;21) or even t(15;17) have been noted in these leukemias. This category has a morphologic presentation similar to the corresponding "de novo" AML and a much more favorable outcome with chemotherapy. , 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.
  • Cytogenetics


    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.
    MORPHOLOGY AND CYTOCHEMISTRY: Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is one of the best known and usually correlates with AML M2, with well defined and specific morphological features. AML M2 FAB is the morphological type predominating in correlation with t(8;21), but some AML M1 or AML M4 cases have been also reported. Rare cases with a low bone marrow blast cell count (<20%) may be distinguished to RAEB and should be include in the AML group with low blast cell count category (see below). AML M2 with t(8;21) are more common in children than adults.
    IMMUNOLOGICAL MARKERS: M2 AML with t(8;21) show frequent co-expression of the B lymphoid marker CD19 with CD33 and CD34 and less often CD56.
    CLINICAL FEATURES: t(8;21) is usually associated with a good response to chemotherapy and a high remission rate with long-term disease-free survival. A large number of patients demonstrate additional chromosome abnormalities: loss of sex chromosome and del(9)(q22); no adverse outcome have been noted for either additional abnormality.Tumoral manifestation such as bony chloromas, may be seen at presentation; in such cases the initial bone marrow aspiration may show a limited and misleadingly low number of blast cells. These should not be confused with MDS. In these particular cases, AML M2 can still be diagnosed even if the morphological features described above are present, although the blasts are below 20% (see below).
    MOLECULAR ANALYSIS: Both heterodimeric components of the core binding factor complex (CBF), CBFalpha (also known as AML1) and CBFbeta are known to be involved in translocations associated with leukemia. The translocation t(8;21)(q22;q22) involves the AML1 (21q22) and ETO (8q22) genes. The AML/ETO - fusion transcript is consistently detected in patients with t(8;21) AML. Disruption of the AML1 gene is clustered within a single intron. AML1 has similarities to the drosophilia segmentation gene RUNT. Some AML M2 patients with the cytological profile described above, demonstrate rearrangement of AML1 and ETO despite being cytogenetically negative for the 8;21 translocation.


    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.
    MORPHOLOGY AND CYTOCHEMISTRY: In addition to the morphological features of AML M4, the bone marrow shows a variable number of eosinophils at all stages of maturation without significant maturation arrest. The most strinking abnormalities involve the immature eosinophilic granules. Whilst the majority of inv(16)(p13q22) have been identified as AML M4EO, this abnormality may occasionally been seen in other myeloid malignancies, including AML M2, M4 without eosinophilia, M5 and MDS.
    IMMUNOPHENOTYPE: Although no specific markers for the monocytic cell line have been identified, some positive markers such as CD14, CD15, CD4, CD11b and CD11c in addition to CD13 and CD33 may be a good indication for monocytic differentiation. In M4 AML with inv(16), co-expression of CD2 with myeloid markers have been demonstrated.
    CLINICAL FEATURES: Convergent studies has revealed that patients with M4 AML with inv(16) and t(16;16) achieved higher complete remission (CR) rates. Conversely del(16q) is different and do not have a better outcome than other M4 AML or MDS. It remains to be defined whether CBFbeta is involved in these deletions.
    MOLECULAR ANALYSIS: Inv(16) and t(16;16) both result in the fusion of the CBFbeta gene at 16q22 to the smooth muscle myosin heavy chain ( MYH11) at 16p13. CBFbeta codes for Core Binding Factor (CBFbeta) sub-unit, a heterodimeric transcription factor known to bind the enhancers of various murine leukemia viruses and similar motifs in the regulatory regions of T cell (TCR), myeloperoxidase, neutrophil elastase and several growth factor receptor gene. The CBFbeta sub-unit is identical to AML1, one of the gene involved in the t(8;21) translocation usually associated with AML M2. Occasionally cytological features of AML M4EO may be present without karyotypic evidence of abnormality of chromosome 16. The CBFbeta/MYH11 is usually demonstrated by molecular studies. Thus, at diagnosis, the use of FISH and RT-PCR methods are important when evaluating inv(16).


    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
    MORPHOLOGY AND CYTOCHEMISTRY. The nuclear size and shape is irregular and highly variable; they are often kidney-shaped or bilobed.The cytoplasm is completely occupied by densely packed or even coalescent granules, staining bright pink, red or purple by MGG. In some cells the cytoplasm is filled with fine dust-like granules. Characteristic cells contain bundle of Auer rods ("faggot cells"). In M3 AML, MPO is always strongly positive in all blast cells. Cases with a similar t(15;17) but with different morphological features, have been subsequently reported and have been called alternatively "M3-variant" AML, or "microgranular" variant. Distinct morphological features such as paucity or absence of granules, and a prominently bilobed nuclear shape characterize them.
    IMMUNOLOGICAL MARKERS: M3 AML with t(15;17) is usually characterized by the association of the lymphoid marker, CD2 and CD19, with myeloid markers and the negativity of HLA-DR and CD34.
    CLINICAL FEATURES: M3/M3-variant AML is frequently associated with disseminated intra-vascular coagulation (DIC). A particular sensitivity to treatment with all-trans retinoic acid (ATRA) has been demonstrated. ATRA act as a differentiation therapy for acute promyelocytic leukemia. The prognostic value of M3 AML/t(15;17) is inferior to t(8;21) and inv(16) and superior to the poor prognostic group (AML with abnormalities of the chromosomes 5 and 7). AML M3 patients are however increasingly treated in independent protocols, rendering such comparison difficult.
    MOLECULAR ANALYSIS: The sensitivity of M3 cells to all-trans retinoic acid led to the discovery that the retinoic acid receptor alpha ( RARalpha) gene on 17q21 fuses with a zinc finger binding transcription factor on 15q22 (promyelocytic leukemia or PML) gene, thus giving rise to a PML-RARalpha fusion gene product. Chromosomal variant of t(15;17). Rare cases lacking the classical t(15;17) have been described either having complex variant translocations involving both chromosomes 15 and 17 with additional chromosome(s), expressing in all studied cases, the PML/RARalpha transcript, or cases where neither chromosome 15 nor chromosome 17 are apparently involved, but with submicroscopic insertion of RARalpha into PML leading to expression of the PML/RARalpha transcript; these latter cases are considered as cryptic or masked t(15;17). Morphological analysis showed no major difference between the t(15;17) positive control group and the PML/RARalpha positive patients without t(15;17).


    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.
    MORPHOLOGY AND CYTOCHEMISTRY: Patients were initially reported as having M3 morphology. Interestingly, the t(11;17)(q23;q21) PLZF/RARalpha subgroup showed clearly morphological differences with predominance of cells with regular nuclei, many granules, usually no Auer rods, increased number of pseudo Pelger-Huet cells and a strong MPO activity. These particular characteristics could allow the definition of a separate morphological entity among APL.
    CLINICAL FEATURES: M3-like patients with t(11;17)(q23;q21) are resistant to ATRA, both in vivo and in vitro.
    MOLECULAR ANALYSIS: In patients with t(11;17)(q23;q21), where RARalpha is fused to the PLZF (promyelocytic leukemia zinc finger) gene, chromosome 17 and RARalpha but not PML are involved.


    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.
    MORPHOLOGY AND CYTOCHEMISTRY: There is a strong association between AML M5/M4 and deletion and translocations involving 11q23. Sometimes cases of 11q23 M5B and M4, and occasionally M2 or M1 also show MLL rearrangement. Two clinical subgroups of patients have a high frequency of 11q23 aberration and M5 subtypes: one is AML in infants with MLL rearrangement in about 50% of cases; the other group is "secondary leukemia" (sAML) potentially after treatment with DNA topoisomerase II inhibitors. In general the translocations in these leukemia are the same as those occurring in "de novo" leukemia i.e.t(9;11), t(11;19).
    MOLECULAR ANALYSIS: The MLL gene on 11q23 is involved in a number of translocations with different partner chromosomes. The most common translocations observed in childhood AML are the t(9;11)(p21;q23) and the t(11;19)(q23;p13.1); other translocations of 11q23 involve at least 50 different partners chromosomes. A partial tandem duplication of MLL gene has also been reported in the majority of adult patients whose leukemic blast cells have a +11 and in some with normal karyotype. Molecular studies have shown that MLL is rearranged more frequently than is revealed by conventional cytognetic studies.


    Second group WHO: mAML : Multilineage AML


    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.


    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.


    Third group WHO: "Secondary AML"


    DEFINITION The term "secondary" AML has been utilized to encompass several different situations.


    Fourth group WHO: Morpholocical and Immunophenotyping classification


    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".

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    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.
    - Recurrent cytogenetic abnormalities are important as prognostic indicators in AML. The identification of specific abnormalities is used increasingly to decide treatment. Cytogenetic findings have contributed to the understanding of morphological and clinical heterogeneity of AML. Molecular genetic analysis of recurrent translocations and inversions has led to clone genes adjacent to chromosome breakpoint and to characterize their protein products involved in the leukemogenesis process.
    - Over the years, leukemia classifications have been mainly descriptive, which was open to regular criticism, revision and reassessment. During the last 20 years, classification according to morphological features of leukemia has been proposed (F.A.B. defined classification). This classification is based on cell morphology on May-Grunwald-Giemsa (MGG) staining of peripheral blood and bone marrow smears with the addition of simple cytochemical techniques

    Rationale for a new classification approach
    - The age-incidence of AML is subtly bimodal. Between early childhood and age 45, the annual incidence of acute myeloid leukemia (AML) remains constant at 0.8 cases/105population. The incidence rises exponentially after the age of 45, exceeding 15 cases/105 population by age 75. AML has been extensively characterized using cytogenetic since the mid-1970s.
    - Available data have suggested an alternative classification in four main groups; a first one for patients identified with specific balanced translocations, the second group for patients with "multilineage" deregulation, a third one for "secondary" AML (after exposure to mutagenic agent or chemo/radiotherapy). Although this is a more rational model of AML classification, some patients cannot be classified into the three first groups and defined a fourth group. At least for the moment, the diagnosis of this last group of patients must rely on the classical cytologic approach (FAB) defining "morphological"-based category.

  • The first group is characterized by recurring chromosomal abnormalities, mainly balanced reciprocal translocations and affects children and young adults. In this group, it is assumed that there is involvement of committed precursor. This may explain the cellular involvement of a specific subset of myeloid cells for example pure granulocytic cells in t(15;17) AML, granulocytic and eosinophilic cells in t(8;21) AML, and monocytes and eosinophils in inv(16). These patients often have a high rate of complete remission with cytotoxic chemotherapy.
  • The second group has similar abnormalities to those which are associated with myelodysplastic syndromes, occur mainly in the elderly population and are rare in childhood. They are characterized by multilineage involvement of bone marrow cells suggesting an early commitment precursor (stem cell). Cytogenetic studies usually show complex chromosome aberrations, mainly loss of genetic material. These diseases are associated with a poor prognosis and a lesser incidence of complete remission after chemotherapy.
  • The third group concerns "secondary" AML (mainly after treatment for malignant diseases) usually morphologically and cytogenetically related with the second group, or more rarely with the first one, depending of the type of triggering drug used.
  • Citation

    Georges Flandrin

    Classification of acute myeloid leukemias

    Atlas Genet Cytogenet Oncol Haematol. 2002-05-01

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