Acute myeloid leukemia (AML) comprises a heterogeneous group of neoplastic disorders in which ≥20% of cells in the blood or bone marrow are myeloblasts. Historically, AML has been classified according to the morphology and immunophenotype but since the 3rd edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, genetic abnormalities have been incorporated in the diagnostic algorithms for AML [1, 2]. Recurrent genetic abnormalities include chromosomal translocations involving transcription factors associated with distinct clinical, morphological, and immunophenotypic features that define a clinicopathological and genetic entity. In the revised 4th edition of the WHO classification published in 2017 , AML is classified into 6 categories: AML with recurrent genetic abnormalities; AML with myelodysplasia-related changes (MRC); therapy-related myeloid neoplasms (t-MN); AML, not otherwise specified (NOS); myeloid sarcoma; and myeloid proliferations related to Down syndrome (DS) (Table 1). This review discusses each of these categories and highlights the initial diagnostic workup necessary for their diagnosis.
This entity includes AML with balanced translocation/ inversions, as well as AML with gene mutations, and accounts for about 20–30% of patients with AML. AML with balanced translocations include t(8;21)(q22;q22.1);
AML with gene mutations is another category under AML with recurrent genetic abnormalities. AML with mutated
The diagnosis of AML-MRC requires that the following criteria are met. First, the blast count in blood or marrow should be ≥20%; second, patients should have a history of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN), or MDS-related cytogenetic abnormality (Table 2) or multilineage dysplasia; and third, patients should not have received prior cytotoxic or radiation therapy for an unrelated disease or have the recurrent cytogenetic abnormalities described for AML with recurrent genetic abnormalities. AML-MRC generally has a poor prognosis with a lower rate of complete remission than other AML subtypes [17, 18]. To diagnose AML-MRC based on morphology, dysplasia must be present in ≥50% of cells in at least two hematopoietic cell lines. Moreover, multilineage dysplasia alone is insufficient to diagnose AML-MRC in a de novo case of AML with mutated
t-MN includes t-AML, t-MDS, t-MDS/MPN, which occur as a complication of cytotoxic therapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Cytotoxic agents implicated in t-MN include alkylating agents, topoisomerase II inhibitors, some antimetabolites, anti-tubulin agents, and radiation therapy. t-MN accounts for 10–20% of all cases of MDS and AML . Regardless of the blast count and morphologic diagnosis, t-MDS and t-AML are included as t-MN, owing to the presence of prior iatrogenic exposure to mutagenic agents and its relation to pathogenesis of the t-MN, although recent studies have suggested some inherited risk factors [24, 25]. The prognosis of t-MN is generally poor, influenced by cytogenetic and genetic mutations, as well as the underlying malignancy for which prior therapy was received [26, 27].
Cases of AML that are not classified into any of the abovementioned categories are classified as AML, NOS. This category classifies AML based on morphology, cytochemistry, and immunophenotype, which was the basis for earlier AML classifications [1, 2]. Subcategories include AML with minimal differentiation, without maturation, with maturation, acute myelomonocytic leukemia, acute monoblastic and monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, and acute panmyelosis with myelofibrosis. Changes have been made for erythroid leukemia and bone marrow with >80% immature erythroid precursors; bone marrow nucleated cells with >30% proerythroblasts is only included in the pure erythroid leukemia category and thus, the myeloblast counts are <20% . Cases previously classified as erythroleukemia (myeloid/erythroid) are now classified as MDS according to the blast count, cytopenia, and dysplasia, because they share greater similarity with MDS than with AML [29, 30].
A tumor mass consisting of myeloid blasts, occurring at a site other than the bone marrow, is diagnosed as myeloid sarcoma. The diagnosis is equivalent to a diagnosis of AML and can precede or coincide with AML [31, 32]. Myeloid sarcoma shows blastic-type as well as monoblastic or myelomonocytic type ; recent studies using next-generation sequencing have identified mutations similar to those implicated in AML, such as
Individuals with DS are known to have increased risk of leukemia [34, 35]. Transient abnormal myelopoiesis (TAM) associated with DS and myeloid leukemia associated with DS are included in this category. TAM is a disorder of newborns with DS that presents with clinical and morphological findings of AML at 3–7 days after birth . Most patients exhibit spontaneous remission but others develop AML after 1–3 years. Most cases of myeloid leukemia associated with DS are acute megakaryoblastic leukemia . In individuals with DS, the distinction between MDS and AML is irrelevant; thus, both are included in the category of myeloid leukemia associated with DS. In addition to trisomy 21, mutations of
Diagnosis of AML according to the revised WHO classification  requires the results of morphological, immunophenotypic, cytogenetic, and molecular genetic testing, as well as prior medical history and clinical information. For adult patients with AML, cytogenetic and molecular genetic testing results are needed to assign AML to the recurrent genetic abnormalities category. Cytogenetic studies, screening for gene rearrangements, and assessment of gene panels including
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