Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis

INTRODUCTION — Acute myeloid leukemia (AML; formerly called acute myelogenous leukemia) refers to a diverse group of aggressive hematologic malignancies involving the proliferation of leukemic blasts committed to the granulocytic, monocytic, erythroid, or megakaryocytic lineages.

AML is characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular elements. As a result, there is an accumulation of leukemic blasts or immature forms in bone marrow, peripheral blood, and occasionally in other tissues, with variable reduction of normal red blood cells, platelets, and mature granulocytes. The decrease in mature elements typically causes symptoms related to cytopenias (eg, fatigue, bleeding, infections) and may result in complications from the large mass of malignant cells. (See "Acute myeloid leukemia: Pathogenesis".)

The clinical presentation, pathologic features, and diagnosis of AML are reviewed here.

The clinical presentation and diagnostic criteria for acute promyelocytic leukemia (APL), a distinctive subtype of AML, are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

The classification, prognosis, cytogenetics, and complications of AML are discussed separately.

●(See "Acute myeloid leukemia: Classification".)

●(See "Acute myeloid leukemia: Risk factors and prognosis".)

●(See "Acute myeloid leukemia: Cytogenetic abnormalities".)

●(See "Acute myeloid leukemia: Overview of complications".)

EPIDEMIOLOGY — AML is the most common acute leukemia in adults and accounts for approximately 80 percent of cases in this age group [1,2]. By contrast, AML accounts for less than 10 percent of acute leukemias in children <10 years.

In the United States, the incidence of AML in 2020 was approximately 4 per 100,000 adults [3]. The incidence increases with age, with a median age of 65 years at diagnosis. The incidence is similar among persons of different races/ethnicities.

Nearly all cases of AML are associated with acquired gene mutations, but the underlying cause is uncertain for most individuals. AML has been associated with environmental factors (eg, exposure to cytotoxic chemotherapy, radiation, chemicals, and tobacco), and, in some cases, it is associated with germline (usually inherited) genetic abnormalities (eg, trisomy 21; Fanconi anemia; germline pathogenic variants of CEBPA, DDX41, and RUNX1). In some patients, AML is preceded by clonal hematopoiesis (CH), such as CH of indeterminate significance (CHIP), myelodysplastic syndromes/neoplasms, myeloproliferative neoplasms, or paroxysmal nocturnal hemoglobinuria.

Further discussion of the pathogenesis of AML are presented separately. (See "Acute myeloid leukemia: Pathogenesis" and "Familial disorders of acute leukemia and myelodysplastic syndromes".)

CLINICAL PRESENTATION — Patients with AML typically present with symptoms related to pancytopenia (anemia, neutropenia, and thrombocytopenia). Some patients present with a tumor mass (myeloid sarcoma) or complications associated with the large burden of malignant blasts.

Medical emergencies that may occur at clinical presentation of AML are discussed below. (See 'Medical emergencies' below.)

●Cytopenia related

•Anemia – Fatigue, pallor, and weakness are common and often precede the diagnosis of AML by months.

•Fever – If fever is present, it is almost always related to infection. Fever in a patient who presents with AML should prompt an investigation for an infectious cause and trigger empiric administration of broad-spectrum antibiotics, particularly if neutropenia (<1000 neutrophils/microL) is present. The management of febrile neutropenia is discussed separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

A small minority of patients have fever related solely to the underlying leukemia that abates with appropriate chemotherapy; this phenomenon may be more common in patients with acute promyelocytic leukemia (APL) [4]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

•Bleeding/bruising – Bleeding and bruising may be related to thrombocytopenia, but qualitative platelet defects and/or coagulopathies may also contribute.

Disseminated intravascular coagulation (DIC) or other coagulopathies can occur with AML and are especially common in patients with APL. The evaluation of DIC in patients with APL is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

●Extramedullary disease – Fewer than 1 percent of patients present with prominent extramedullary disease, such as myeloid sarcoma (chloroma) or infiltration of skin or gingiva [5]. Extramedullary disease may present simultaneously with or precede bone marrow disease. Mucocutaneous infiltration is most often seen when there is a prominent monocytic component to the leukemia. Myeloid sarcoma may involve bone, periosteum, soft tissues, and lymph nodes; less often, the orbit, intestine, mediastinum, epidural region, uterus, and ovary are involved [6-10].

●Bone/joint pain – Bone pain is uncommon in adults with AML, although individuals may describe sternal discomfort or tenderness, occasionally with aching in the long bones. This may be especially severe in the lower extremities due to expansion of the medullary cavity by the leukemic process. Joint pain (eg, symmetric or migratory polyarthritis/arthralgia) occurs in <5 percent of patients with AML. Multiple processes can contribute to joint symptoms, such as gout, pseudogout, infection, and/or direct synovial infiltration with leukemic cells. Joint disease in AML is discussed separately. (See "Malignancy and rheumatic disorders", section on 'Leukemia' and "Acute myeloid leukemia: Overview of complications", section on 'Joint involvement' and "Monoarthritis in adults: Etiology and evaluation".)

●Skin – Examination of the skin can reveal pallor due to anemia, petechiae or ecchymoses secondary to thrombocytopenia or DIC, or infiltrative lesions suggestive of leukemic involvement (leukemia cutis or myeloid sarcoma). Leukemic involvement of the skin occurs in up to 13 percent of patients and is most often found in patients with AML with a prominent monocytic or myelomonocytic component (picture 1) [11,12]. The lesions are often nodular and violaceous/gray-blue in color. Rarely, cases of leukocytoclastic vasculitis have been reported [13]. The presence of erythematous or violaceous tender nodules and plaques suggests acute neutrophilic dermatosis (eg, Sweet syndrome). (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

●Oropharynx – An examination of the oropharynx may reveal leukemic involvement (eg, gingival hypertrophy, especially with monocytic subtypes (picture 2) [14]), oral candidiasis, or herpetic lesions.

●Eyes – An examination of the ocular fundus may reveal hemorrhages and/or whitish plaques, and the conjunctivae may be pale, in association with anemia. (See "Acute myeloid leukemia: Overview of complications", section on 'Ocular involvement'.)

●Central nervous system – The precise incidence of central nervous system (CNS) involvement at the time of diagnosis is unknown since evaluation of the CNS (eg, imaging, lumbar puncture) is not routinely performed unless there are neurologic abnormalities. CNS involvement is more common in patients with AML with a prominent monocytic component, hyperleukocytosis, or children <2 years [15,16]. Marked elevations of lactate dehydrogenase and abnormalities of chromosomes 11 and 16 have also been associated with CNS disease at presentation or relapse [17]. CNS involvement is discussed in greater detail separately. (See "Acute myeloid leukemia: Involvement of the central nervous system".)

CNS evaluation in patients with unexplained neurologic abnormalities is discussed below. (See 'Neurologic' below.)

●Organomegaly – Hepatomegaly and/or splenomegaly are present in approximately 10 percent of cases and, if found, may suggest the possibility of acute lymphoblastic leukemia or evolution of AML from a prior myeloproliferative neoplasm (eg, blast crisis of chronic myeloid leukemia) [18]. Palpable adenopathy is uncommon in patients with AML, and significant lymph node enlargement is rare.

MEDICAL EMERGENCIES — Some patients with AML present with medical emergencies related to the proliferation of malignant blasts, tumor masses, or cytopenias.

Hyperleukocytosis/leukostasis — Hyperleukocytosis is defined by a white blood cell (WBC) count >100,000/microL, which can be associated with leukostasis, a complex of symptoms or signs of end-organ damage that most often affects the central nervous system (CNS) or the lungs. Hyperleukocytosis and leukostasis are uncommon presentations of de novo AML.

Respiratory, neurologic, and other end-organ leukostatic effects constitute a medical emergency. The evaluation and management of hyperleukocytosis and leukostasis are discussed separately. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

Neurologic complications — Neurologic abnormalities in a patient presenting with AML may be caused by CNS hemorrhage, tumor mass (myeloid sarcoma), leukemic meningitis, or other causes. Evaluation of the CNS in a patient with AML who presents new neurologic abnormalities is discussed below. (See 'Neurologic' below.)

Metabolic and electrolyte abnormalities — Patients can present with various metabolic and electrolyte abnormalities, many of which are due to the high turnover of the proliferating leukemic cells. Tumor lysis syndrome is an oncologic emergency that should be suspected in patients with hyperphosphatemia, hypocalcemia, hyperuricemia, and/or hyperkalemia. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Other metabolic derangements that can be seen in patients with AML include hypokalemia and lactic acidosis. Metabolic abnormalities in AML are described in more detail separately. (See "Acute myeloid leukemia: Overview of complications", section on 'Metabolic abnormalities'.)

Bleeding/hemorrhage — Bleeding or hemorrhage at presentation of AML may be due to thrombocytopenia, qualitative platelet defects, and/or coagulopathies.

Bleeding due to disseminated intravascular coagulation (DIC) is most common with acute promyelocytic leukemia (APL). The evaluation and management of DIC in patients with APL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

EVALUATION — A patient with suspected AML requires clinical evaluation, laboratory studies, pathology (ie, morphology, immunophenotype, cytogenetic/molecular studies), and other evaluations, as clinically indicated.

Evaluation should be performed according to 2022 European LeukemiaNet guidelines [19] and College of American Pathologists and American Society of Hematology (CAP-ASH) guidelines [20].

Clinical and laboratory

●Clinical – History should evaluate symptoms related to cytopenias (eg, fatigue, dyspnea, infections, bleeding) and neurologic symptoms. Examination should seek evidence of mucocutaneous infiltration or bleeding, organomegaly, and extramedullary collections of leukemic blasts.

●Laboratory

•Hematology – Complete blood count (CBC) with leukocyte differential count, review of a blood smear, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen

•Chemistries – Comprehensive metabolic panel, lactate dehydrogenase, uric acid

High numbers of metabolically active circulating leukocytes can interfere with certain laboratory tests. Examples include decreased serum glucose, hyperkalemia, and hypoxemia. Spurious hyperkalemia can be caused by the release of potassium due to cell lysis (eg, from clotting) and/or mechanical issues (eg, delayed processing, transportation through a pneumatic tube); special attention should be paid when handling these specimens. Hypoxemia in an arterial blood gas may be seen with normal arterial oxygen saturation levels on pulse oximetry; blood sent for blood gas assessment should be transported in ice [21].

●Imaging – Imaging is not routinely required for patients who present with AML but should be performed to evaluate neurologic abnormalities or extramedullary disease, as clinically indicated.

•Extramedullary disease – Positron emission tomography (PET)/computed tomography (CT) is performed to evaluate a patient with suspected myeloid sarcoma.

•Imaging to evaluate neurologic abnormalities is described below. (See 'Neurologic' below.)

Neurologic — Evaluation of the central nervous system (CNS) is required for patients with unexplained neurologic findings, but it is not otherwise routinely performed.

●Imaging – Brain CT without contrast is performed if CNS hemorrhage is suspected. Brain magnetic resonance imaging (MRI) with contrast should be performed if leukemic meningitis is suspected.

●Lumbar puncture (LP) should be performed if the patient has findings that suggest leukemic meningitis. Brain CT should be performed prior to the LP to exclude a CNS mass or hemorrhage.

The administration of a single dose of intrathecal (IT) chemotherapy with methotrexate or cytarabine may be considered at the time the diagnostic LP is performed.

Further details of the evaluation and management of CNS involvement are discussed separately. (See "Acute myeloid leukemia: Involvement of the central nervous system".)

Pathology evaluation — Diagnosis of AML requires pathologic confirmation that the leukemic blasts are myeloid in origin.

The pathology evaluation should integrate morphology from peripheral blood and bone marrow with flow cytometry and genetic studies. In most cases, evaluation of a bone marrow aspirate is required for a definitive diagnosis, but in some cases findings from peripheral blood or an extramedullary mass are sufficient to evaluate, diagnose, and classify AML [19,22,23]. Pathologic findings of AML blasts are described below. (See 'Pathologic features' below.)

●Blood – CBC with differential count and review of a blood smear are used to evaluate circulating blasts and determine the blast percentage.

When circulating blasts are abundant, a blood specimen can be evaluated for flow cytometry and for cytogenetic/molecular analysis, in lieu of a bone marrow examination.

Pathologic findings of AML in blood are described below. (See 'Peripheral blood' below.)

●Bone marrow – A unilateral bone marrow aspirate and biopsy is sufficient for the evaluation of AML. The laboratory should be notified at the time of the procedure, as multiple studies need to be performed on freshly obtained specimens.

The preferred site in adults is the posterior superior iliac crest, although a different site should be used if the patient previously received irradiation to this area. The sternum is a reasonable alternative site for bone marrow aspiration, but a bone marrow biopsy cannot be performed at the sternum.

It is unusual to have bleeding or infection develop at the site of the procedure, even in patients with neutropenia, thrombocytopenia, and/or coagulopathy. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Choice of aspiration or biopsy site'.)

•Aspirate

-Microscopy – A Wright-Giemsa-stained specimen is used to assess cytomorphology of the leukemic blasts and nonmalignant bone marrow constituents. Cytomorphologic features of myeloid blasts are described below. (See 'Cytomorphology' below.)

-Blast percentage – A 500-cell differential count should be performed to calculate the percentage of blasts in the bone marrow. The blast percentage should include myeloblasts and "blast equivalents," such as neoplastic promyelocytes and promonocytes.

Flow cytometry is not an adequate substitute for the morphologic differential count, as the blast percentage may be influenced by hemodilution, specimen preparation (eg, red cell lysis technique, density gradient centrifugation), and gating criteria for different cell populations.

-Immunophenotyping – Flow cytometry is used to determine the blast lineage. Immunophenotypic findings in AML are described below. (See 'Immunophenotype' below.)

-Cytogenetic/molecular analysis – Cytogenetic and molecular findings are essential aspects of the diagnostic evaluation and classification of AML. (See 'Cytogenetic/molecular abnormalities' below.)

All patients with suspected AML should undergo metaphase chromosome banding analysis of bone marrow, blood, or myeloid sarcoma. Fluorescence in situ hybridization (FISH) can detect certain karyotypic abnormalities, but it is not an adequate substitute for chromosomal banding. Next generation sequencing myeloid gene panels have largely replaced polymerase chain reaction (PCR) and other approaches for identifying mutations in AML.

Cytogenetic and molecular features that are used for diagnosis and subtype classification of AML are described below. (See 'Diagnosis' below.)

-Other studies – Aspirate smears can also be used for iron staining (which is useful for identifying ring sideroblasts in AML with myelodysplastic features) and for cytochemical reactions (if performed). Infectious disease studies for mycobacteria, yeast, or fungi should be performed, if clinically indicated.

•Biopsy

-Morphology – The bone marrow biopsy gives an overview of the degree of involvement by leukemic blasts.

Fixed, decalcified, and sectioned specimens are stained with hematoxylin and eosin, reticulin, and/or immunohistochemical/cytochemical stains (if needed). Pathologic findings are described below. (See 'Cytomorphology' below.)

-Other studies – If aspiration resulted in a "dry tap" (usually due to a hypercellular marrow packed with blasts or extensive fibrosis), a portion of the biopsy specimen can be used for ancillary studies. Touch preparations of the core can be prepared with Wright-Giemsa stain for cytomorphology, while additional material can be submitted in culture medium (Roswell Park Memorial Institute culture medium) or saline for flow cytometry, cytogenetic, and molecular analyses.

PATHOLOGIC FEATURES — An experienced hematopathologist should review the pathologic features of AML blasts, whenever possible.

Peripheral blood — In most patients, AML is apparent by morphologic and/or immunophenotypic findings from peripheral blood. In some cases, a diagnosis of AML can be made using findings from peripheral blood without a bone marrow examination. (See 'Diagnosis' below.)

●Blood counts – The median leukocyte count at diagnosis is approximately 15,000 cells/microL; 20 percent of patients have a leukocyte count >100,000 cells/microL (>100 x 10⁹/L), and 25 to 40 percent of patients have <5000 leukocytes/microL.

Most patients have variable degrees of a normocytic, normochromic anemia. The reticulocyte count is normal or decreased. Approximately three-quarters of patients have <100,000 platelets/microL at diagnosis, while one-quarter have <25,000 platelets/microL.

●Morphology – Nearly all patients with AML have circulating myeloblasts that can be detected on peripheral smear. Automated hematology analyzers generate flags for when they detect suspected blasts and other abnormal cell types that should trigger review of morphology by the technical staff or a hematopathologist. Morphologic features of myeloid blasts are described below. (See 'Bone marrow' below.)

●Immunophenotype – Flow cytometry can characterize circulating myeloblasts in most patients based on patterns of surface antigen expression (table 1) [24]. Where available, a positive myeloperoxidase (MPO) cytochemical reaction can quickly determine if the blasts are myeloid, but flow cytometry has largely replaced enzyme cytochemistry for lineage assignment. Immunophenotypic findings of myeloid blasts are described below. (See 'Immunophenotype' below.)

Bone marrow

Cytomorphology — Bone marrow is usually hypercellular, with partial or nearly total replacement of normal cellular constituents by leukemic blasts. Some cases of AML present with a hypocellular bone marrow.

●Aspirate smear – Wright-Giemsa-stained myeloblasts typically appear as immature cells with large nuclei, prominent nucleoli, and a variable amount of pale blue cytoplasm that may include faint granulation (picture 3). Prominent cytoplasmic granules may be seen in acute promyelocytic leukemia (APL). Auer rods are pink or red rod-like granular cytoplasmic structures that are pathognomonic for AML. The nuclear to cytoplasmic ratio, cytomorphology, and presence of Auer rods vary among AML subtypes.

Some cases of AML display morphologic evidence of myelodysplasia in residual maturing cells.

●Biopsy – The bone marrow biopsy provides an overview of the degree of involvement by leukemic blasts. The hematoxylin-eosin-stained biopsy specimen is generally infiltrated with a monotonous leukemic (blast) population. Other stains may reveal various histologic features associated with AML, such as fibrosis or necrosis.

Immunophenotype — AML blasts must have immunophenotypic features of myeloid, monocytic, erythroid, or megakaryocytic lineages.

The specific immunophenotypic pattern differs among AML subtypes, but most cases express CD34, HLA-DR, CD117, MPO, CD13, and CD33 (table 1). If cytochemical staining is performed, myeloid blasts may be positive for MPO, chloroacetate esterase, or nonspecific esterase.

Up to one-fifth of AML specimens can have limited coexpression of lymphoid markers (eg, CD7, CD19, CD79a, PAX5, CD2, CD4). This is seen most often in particular AML subtypes, such as CD19 expression in AML with RUNX1::RUNX1T1 or CD2 expression in APL.

Cytogenetic/molecular abnormalities — Cytogenetic and/or molecular abnormalities are found in nearly all cases of AML. These findings are required for contemporary diagnosis and classification of AML [22,23].

One-half of cases of newly diagnosed AML demonstrate chromosomal abnormalities, such as reciprocal chromosomal rearrangements, trisomy, monosomy, or multiple abnormalities. Next generation sequencing detects mutations in >95 percent of cases of AML [25]. Cytogenetic and molecular features that are used for diagnosis and subtype classification of AML are described below. (See 'Diagnosis' below.)

Additional details of cytogenetic features of AML and associated clinical presentations are presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities".)

Detection of certain mutations, such as FLT3 and IDH1/2, may affect the choice of induction therapy for AML, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Acute myeloid leukemia: Management of medically unfit adults".)

DIAGNOSIS — AML should be suspected in patients with circulating abnormal/immature leukocytes and/or unexplained findings related to cytopenias, bone pain, hyperleukocytosis, tumor lysis syndrome, or other AML-related medical emergencies. AML may also be suspected in patients with such clinical presentations who do not have blasts on a blood smear.

Diagnosis requires confirmation of the myeloid origin of leukemic blasts, based on cytomorphologic, immunophenotypic, cytogenetic, and molecular findings. Diagnosis is usually based on analysis of bone marrow specimens, but in some cases, peripheral blood and/or a myeloid sarcoma can provide adequate diagnostic material without the need for a bone marrow examination.

Morphologic and immunophenotypic features of myeloid blasts are discussed above. (See 'Pathologic features' above.)

Two new classification schemes for AML were published in 2022; either or both of the following can be used to diagnose and classify AML:

●International Consensus Classification (ICC) [22]

●World Health Organization Classification 5^th edition (WHO5) [23]

Both ICC and WHO5 rely heavily on cytogenetic and molecular findings to diagnose and classify AML. They replace earlier classification systems that used cytomorphology and limited immunophenotypic and cytogenetic findings. Where there are differences between the ICC and WHO5 classification systems, they are generally minor and do not affect patient management.

●For most cases of AML, the ICC and WHO5 systems apply the same diagnostic criteria and labels. (See 'ICC and WHO5 consensus criteria' below.)

●For other AML subtypes, diagnostic criteria and labels differ between ICC and WHO5, as discussed below. (See 'Differences in ICC and WHO5 criteria/labels' below.)

Importantly, both ICC and WHO5 recognize that the presence of certain genetic findings does not require >20 percent myeloid blasts to establish the diagnosis of AML. Additional details of the ICC and WHO5 classification systems for hematologic malignancies are described separately. (See "Classification of hematopoietic neoplasms".)

ICC and WHO5 consensus criteria — Both International Consensus Classification (ICC) and World Health Organization Classification 5^th edition (WHO5) define blasts as myeloid according to morphologic and immunophenotypic features, as described above. (See 'Pathologic features' above.)

ICC and WHO5 apply identical (or very similar) diagnostic criteria and labels for cases of AML in which myeloid blasts have any of the following cytogenetic/molecular findings [22,23].

●Defining genetic abnormalities – Most cases of AML have defining genetic abnormalities.

Specifically, both ICC and WHO5 recognize the following genetic abnormalities as AML-defining even with <20 percent blasts [22,23]:

•Acute promyelocytic leukemia – t(15;17)(q24.1;q21.2)/PML::RARA or other RARA rearrangements

•AML with in-frame basic leucine zipper (bZip) domain CEBPA mutation

•t(8;21)(q22;q22), RUNX1::RUNX1T1

•inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11

•t(9;11)(p21.3;q23.3); MLLT3::KMT2A or other KMT2A rearrangements

•AML with t(6;9)(p22.3;q34.1)/DEK::NUP214

•inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2;MECOM or other MECOM rearrangements

●Other defining genetic abnormalities – Different blast thresholds are applied for cases with the following molecular findings [22,23]:

•AML with BCR::ABL1 requires ≥20 percent blasts.

•AML with mutated NPM1 can be diagnosed irrespective of the blast count if there is appropriate clinicopathologic correlation.

●Myeloid sarcoma – Both ICC and WHO5 define an extramedullary collection of myeloid blasts (myeloid sarcoma) as AML if the blasts satisfy morphologic, immunophenotypic, and/or defining cytogenetic features of AML [22,23].

●Therapy-related myeloid neoplasms – ICC and WHO5 recognize the role of exposure to prior cytotoxic and radiation therapy for another condition in the pathogenesis of myeloid malignancies, but they are labeled and categorized differently [22,23].

Diagnosis and classification of therapy-related AML are discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis", section on 'Diagnosis and classification'.)

●AML with germline predisposition – ICC and WHO5 apply the same diagnostic criteria for AML with germline predisposition, but they are labeled and categorized differently [22,23]. Cases of AML in association with predisposing germline gene variants include the following:

•Down syndrome/trisomy 21

•Myeloid malignancies with germline pathogenic variants of CEBPA, DDX41, TP53, RUNX1, ANKRD26, ETV6, GATA2, SAMD9, or SAMD9L

•Various bone marrow failure syndromes, including Fanconi anemia, Schwachman-Diamond syndrome, telomere biology disorders (eg, dyskeratosis congenita), severe congenital neutropenia, Blackfan-Diamond anemia

AML with germline predisposition is discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Differences in ICC and WHO5 criteria/labels — The International Consensus Classification (ICC) and World Health Organization Classification 5^th edition (WHO5) systems apply different diagnostic criteria, labels, and/or categories for certain AML subsets.

ICC created a new category, called myelodysplastic syndrome/neoplasm (MDS)/AML, for certain subsets in which there are 10 to 19 percent blasts [22]. (See "Acute myeloid leukemia: Classification", section on 'Other AML subtypes in International Consensus Classification'.)

Diagnostic criteria differ between ICC and WHO5 in cases of AML with the following features:

●No defining genetic abnormalities – Cases of AML with no defining genetic abnormalities require ≥20 percent myeloid blasts in both systems, but the ICC and WHO5 differ in how they classify these cases [22,23]:

•ICC – The category AML, not otherwise specified (NOS) requires ≥20 percent myeloid blasts [22]. Such cases with 10 to 19 percent blasts are labeled MDS/AML, NOS. (See "Acute myeloid leukemia: Classification", section on 'Other AML subtypes in International Consensus Classification'.)

•WHO5 – Cases with ≥20 percent myeloid blasts and no defining genetic abnormalities are classified according to the degree of morphologic differentiation. The category, AML, NOS was eliminated.

Details of the morphologic classification of such cases of AML are discussed separately. (See "Acute myeloid leukemia: Classification", section on 'Other AML subtypes in World Health Organization 5th edition'.)

●Mutated TP53

•ICC – Cases with ≥20 percent myeloid blasts in marrow or blood and any TP53 mutation with variant allele frequency (VAF) ≥10 percent are labeled AML with mutated TP53 [22]. Cases with 10 to 19 percent blasts and TP53 mutation with VAF ≥10 percent are labeled MDS/AML with mutated TP53.

•WHO5 – Cases with ≥20 percent blasts plus any TP53 mutation are diagnosed and categorized according to other cytogenetic/molecular features; a classification modifier is added if there was prior cytotoxic treatment or a germline predisposition, such as Li-Fraumeni syndrome [23].

●AML with myelodysplasia-related mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2)

•ICC – AML is diagnosed with ≥20 percent blasts plus ≥1 of the myelodysplasia-related mutations listed above or mutated RUNX1 [22]. Such cases with 10 to 19 percent blasts are labeled MDS/AML with myelodysplasia-related mutations.

•WHO5 – AML is diagnosed with ≥20 percent blasts plus ≥1 of the above mutations [23].

●AML with myelodysplasia-related cytogenetic abnormalities

•ICC – AML is diagnosed with ≥20 percent myeloid blasts that have a complex karyotype (≥3 unrelated clonal chromosomal abnormalities in the absence of other class-defining recurring genetic abnormalities), del(5q)/t(5q)/add(5q), -7/del(7q), +8, del(12p)/t(12p)/add(12p), i(17q), -17/add(17p) or del(17p), del(20q), and/or idic(X)(q13) clonal abnormalities [22]. Such cases with 10 to 19 percent blasts are labeled MDS/AML with myelodysplasia-related cytogenetic abnormalities.

•WHO5 – AML is diagnosed with ≥20 percent blasts plus ≥1 of the above cytogenetic abnormalities, but WHO5 does not include +8 as one of the defining abnormalities [23].

●Acute erythroid leukemia

•ICC – Acute erythroid leukemia (AEL) was eliminated as a distinct subtype in the ICC system [22]. Cases with ≥20 percent blasts with predominantly erythroid features that have a TP53 mutation (VAF ≥10 percent) are diagnosed as AML with TP53 mutation, which accounts for most of what was formerly labeled AEL.

•WHO5 – Cases with predominantly erythroid blasts (usually ≥80 percent of bone marrow elements, of which ≥30 percent are proerythroblasts or pronormoblasts) are diagnosed as AEL without a requirement for ≥20 percent blasts [23].

●Other rare genetic abnormalities – There are very minor differences in this category.

•ICC – Cases with ≥10 percent blasts and rare recurring translocations are included in a category called AML with other rare recurring translocations [22].

•WHO5 – Cases with ≥10 percent myeloid blasts and RBM15::MRTFA fusion or NUP98 rearrangement are considered distinct subtypes in WHO5 [23].

DIFFERENTIAL DIAGNOSIS — AML must be distinguished from other causes of leukocytosis (other leukemias, leukemoid reactions), abnormal circulating myeloid cells (eg, leukemias, megaloblastosis), cytopenias (aplastic anemia, vitamin deficiencies), and certain tumor masses.

Other leukemias — The clinical presentation and leukemic blasts of the heterogeneous subtypes of AML can resemble those of other leukemias.

Pathologic findings should be reviewed by an expert hematopathologist when possible.

AML must be distinguished from other hematologic malignancies, including the following:

●Myelodysplastic syndromes/neoplasms – Many experts view myelodysplastic syndromes/neoplasms (MDS) and AML as components of a spectrum of myeloid malignancies because of shared clinical and pathologic features. In most cases, AML has a higher percentage of blasts than MDS, and there are certain cytogenetic features that are diagnostic for AML. Nevertheless, their similarities are recognized by the new category (MDS/AML) in the International Consensus Classification (ICC) [22]. The World Health Organization 5^th edition recognizes the shared clinicopathologic features of MDS and AML but distinguishes them by blast counts and cytogenetic features [23].

Distinctions between AML and MDS are discussed above. (See 'Diagnosis' above.)

●Acute lymphoblastic leukemia – Acute lymphoblastic leukemia (ALL) is diagnosed based on cytomorphology (eg, absent cytoplasmic granules/Auer rods), immunophenotype (eg, B or T cell antigen expression and limited or no expression of myeloid antigens), and cytogenetic/molecular findings that differ from AML. Details of the pathologic features of ALL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

●Acute leukemias of mixed or ambiguous lineage – These include acute undifferentiated leukemia (AUL) and mixed phenotype acute leukemia (MPAL). AUL and MPAL can generally be distinguished from AML based on immunophenotype and/or genetic alterations. As examples, variable expression of lineage-associated antigens and cytochemical studies can be helpful, while identification of defining genetic alterations, such as BCR::ABL1; KMT2A, ZNF384, or BCL11B rearrangements, can distinguish these leukemias from AML, as discussed separately. (See "Mixed phenotype acute leukemia".)

●Blastic plasmacytoid dendritic cell neoplasm – Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive disorder derived from plasmacytoid dendritic cells. BPDCN often presents with cutaneous lesions, and the blasts can resemble those of AML (or ALL). However, BPDCN can be distinguished based on immunophenotype, which includes expression of CD123, CD4 and/or CD56, and one or more plasmacytoid dendritic cell-associated antigens, as discussed separately. (See "Blastic plasmacytoid dendritic cell neoplasm".)

●Chronic myeloid leukemia blast crisis – The blasts of chronic myeloid leukemia (CML) blast crisis (BC) can resemble those of AML or ALL. The distinction between CML-BC and AML is relatively straightforward when CML-BC arises from chronic phase CML. However, when CML-BC presents de novo, the distinction is more challenging and requires t(9;22)/Philadelphia chromosome and/or BCR::ABL1 in >20 percent of cells. The diagnosis and management of CML-BC are discussed separately. (See "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

●Down syndrome/trisomy 21 – Infants with Down syndrome (DS) can present with transient abnormal myelopoiesis (TAM), in which circulating megakaryoblastic cells are detected in the first months of life; TAM spontaneously regresses in most cases. Children with DS are at an increased risk for a distinctive form of AML called myeloid leukemia of DS (ML-DS) and other leukemias. ML-DS is distinguished from AML by the detection of trisomy 21, mutated GATA1, and other clinicopathologic features, and it requires distinctive management. TAM and ML-DS are discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)" and "Myeloid leukemia associated with Down syndrome (ML-DS)".)

Other conditions — Nonmalignant conditions can manifest clinical features (eg, cytopenias, leukocytosis, tumor masses) and/or abnormal circulating leukocytes that resemble AML. The differential diagnosis includes:

●Megaloblastic anemia – Deficiency of vitamin B12 or folate can cause megaloblastic leukocytes and profound cytopenias that can occasionally be confused with AML. These conditions are distinguished from AML by the measurement of vitamin levels in blood. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

●Aplastic anemia – Immune-mediated aplastic anemia can cause cytopenias in children and adults that may resemble the clinical presentation of AML. Aplastic anemia is distinguished from AML by bone marrow hypoplasia/aplasia and the absence of AML-defining cytogenetic findings. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

●Inherited/germline bone marrow failure syndromes – Fanconi anemia, Schwachman-Diamond syndrome, telomere biology disorders, and other inherited/germline conditions can cause cytopenias that resemble AML. Many are associated with somatic findings (eg, skeletal abnormalities, organ dysfunction) that distinguish them from AML, and they are diagnosed based on the detection of germline genetic gene variants. This contrasts with AML, in which acquired mutations are found only in hematopoietic cells. It is important to note that various types of inherited/germline bone marrow failure syndromes (IBMFS) are associated with an increased incidence of AML that requires distinctive management. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

●Leukemoid reactions – Leukemoid reactions are robust reactive responses to inflammatory conditions, such as severe infections, which can present with significant leukocytosis and immature circulating myeloid forms. Leukemoid reactions are distinguished from AML by the clinical setting, the lower percentage of circulating blasts and promyelocytes, and the absence of a block in differentiation.

●Tumor masses – AML that presents as myeloid sarcoma can clinically and pathologically resemble other tumor masses, especially "small, round blue cell tumors," such as Ewing sarcoma, ALL, and others. Myeloid sarcoma should be suspected if eosinophilic myelocytes are seen on biopsy specimen and is diagnosed according to morphologic, immunophenotypic, and cytogenetic features that are described above. (See 'Pathologic features' above.)

CLASSIFICATION — All cases of AML should be classified into the appropriate subtype. The management and prognosis of AML are affected by cytogenetic and mutational features that are used to classify AML [19].

As discussed above, the International Consensus Classification (ICC) and World Health Organization 5^th edition (WHO5) are both organized with a focus on cytogenetic and molecular findings. (See 'Diagnosis' above.)

Most cases and subtypes of AML receive the same labels in ICC and WHO5, but there are important differences between the two systems, as discussed separately. (See "Acute myeloid leukemia: Classification".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acute myeloid leukemia (AML) (The Basics)")

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY

●Description – Acute myeloid leukemia (AML) is a heterogenous group of hematologic malignancies with leukemic blasts committed to myeloid lineages.

●Epidemiology – AML accounts for 80 percent of acute leukemias in adults (median age 65 years). AML represents <10 percent of acute leukemias in children <10 years. (See 'Epidemiology' above.)

●Presentation – Patients typically present with fatigue, dyspnea, fever, and/or bleeding related to low blood counts. Others present with myeloid sarcoma (extramedullary collections of leukemic blasts) or are asymptomatic and identified by abnormal laboratory studies. (See 'Clinical presentation' above.)

●Medical emergencies – Some patients present with respiratory or neurologic symptoms due to leukostasis, hemorrhage from thrombocytopenia or coagulopathy, or metabolic complications (tumor lysis syndrome). (See 'Medical emergencies' above.)

●Evaluation (see 'Evaluation' above)

•Clinical and laboratory – History includes cytopenia-related symptoms, neurologic abnormalities, prior hematologic disorders, or cytotoxic treatments. The patient is examined for bleeding/bruising, tumor masses, mucocutaneous infiltration, and organomegaly. Complete blood count/differential count, review of the blood smear, and comprehensive metabolic panel are required. Imaging is not routinely performed unless clinically indicated. (See 'Clinical and laboratory' above.)

•Neurologic – Imaging of the central nervous system and lumbar puncture are performed for patients with unexplained neurologic abnormalities. (See 'Neurologic' above.)

•Pathology – Bone marrow aspirate/biopsy, blood, and/or myeloid sarcoma are evaluated by microscopy, flow cytometry, and cytogenetic/molecular studies. (See 'Pathology evaluation' above.)

●Pathologic findings – An experienced hematopathologist should review pathologic features whenever possible. (See 'Pathologic features' above.)

Myeloblasts are typically immature cells with large nuclei, prominent nucleoli, and variable amounts of pale blue cytoplasm that may include faint granulation (picture 3). Auer rods are pathognomonic. Bone marrow biopsy is usually hypercellular with replacement of most normal cellular constituents by blasts. (See 'Cytomorphology' above.)

●Diagnosis – AML should be suspected in patients with circulating abnormal/immature leukocytes and/or unexplained cytopenias, bone pain, hyperleukocytosis, tumor lysis syndrome, or other related medical emergencies. (See 'Diagnosis' above.)

Diagnosis requires demonstration of myeloid blasts by microscopy, immunophenotyping, and cytogenetic findings according to either (or both) International Consensus Classification (ICC) or World Health Organization Classification 5^th edition (WHO5) criteria.

●Consensus diagnostic criteria – ICC and WHO5 diagnostic criteria are the same for the following subtypes (see 'ICC and WHO5 consensus criteria' above):

•Myeloid sarcoma – An extramedullary mass of myeloid blasts that effaces normal tissue architecture.

•The following require ≥10 percent myeloid blasts in marrow or blood and one of the following (see 'Diagnosis' above):

-Acute promyelocytic leukemia – t(15;17)/PML::RARA

-CEBPA mutation

-t(8;21)/RUNX1::RUNX1T1

-inv(16) or t(16;16)/CBFB::MYH11

-t(9;11)/MLLT3::KMT2A

-AML with t(6;9)/DEK::NUP214

-inv(3) or t(3;3)/GATA2;MECOM

The blast threshold differs for AML with BCR::ABL1 (≥20 percent blasts) and AML with mutated NPM1 (no required blast threshold).

●ICC/WHO5 differences – The following generally require ≥20 percent blasts; further details are discussed above (see 'Differences in ICC and WHO5 criteria/labels' above):

•No defining genetic abnormalities

•Mutated TP53

•AML with myelodysplasia-related mutations/cytogenetic abnormalities

•Acute erythroid leukemia

•Other rare genetic abnormalities

●Classification – Classification is according to ICC and WHO5 criteria, as discussed separately. (See "Acute myeloid leukemia: Classification".)

●Differential diagnosis – AML must be distinguished from various acute leukemias and other causes for bone marrow failure, leukocytosis, and tumor masses. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Anastasi, MD, who contributed to earlier versions of this topic review.