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Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia

Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia
Literature review current through: Jan 2024.
This topic last updated: May 24, 2022.

INTRODUCTION — Acute myeloid leukemia (AML; formerly called acute myelogenous leukemia) refers to a diverse group of aggressive hematologic malignancies involving proliferation of myeloid 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 more mature cellular elements. As a result, there is an accumulation of leukemic blasts or immature forms in the bone marrow, peripheral blood, and occasionally in other tissues, with a variable reduction in the production of normal red blood cells, platelets, and mature granulocytes. The increased production of malignant cells, along with a reduction in these mature elements, results in a variety of systemic consequences including anemia, bleeding, and an increased risk of infection. (See "Acute myeloid leukemia: Pathogenesis".)

The presenting signs and symptoms and diagnosis of AML will be reviewed in this topic. The subclassification, prognosis, cytogenetics, treatment, and complications of AML and issues related to one of the AML variants, acute promyelocytic leukemia (AML-M3), 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: Induction therapy in medically fit adults".)

(See "Acute myeloid leukemia: Management of medically unfit adults".)

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

(See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

EPIDEMIOLOGY — AML is the most common acute leukemia in adults and accounts for approximately 80 percent of cases in this age group [1,2]. In contrast, AML accounts for less than 10 percent of acute leukemias in children less than 10 years of age. In the United States and Europe, the incidence is reported as 3 to 5 cases per 100,000 population [3-5].

In adults, the median age at diagnosis is approximately 65 years. The incidence increases with age with approximately 2 and 20 cases per 100,000 population for those under or over 65 years, respectively [6]. The male:female ratio is approximately 5:3. This incidence is similar among persons of different race/ethnicity. In one study, non-Hispanic White Americans had the highest incidence (4 cases per 100,000 population), while Hispanic White and Black Americans, and Asian-American or Pacific Islanders had a slightly lower incidence (3 cases per 100,000 population) [7].

AML has been associated with environmental factors (eg, exposure to chemicals, radiation, tobacco, chemotherapy) and genetic abnormalities (eg, trisomy 21; Fanconi anemia; Bloom's syndrome; familial mutations of CEBPA, DDX41, RUNX1). In some patients, evolution to AML is preceded by evidence of clonal hematopoiesis manifest as myelodysplastic syndrome, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, and aplastic anemia. Details regarding these associations and the pathogenesis of AML are presented separately. (See "Acute myeloid leukemia: Pathogenesis", section on 'Two-hit hypothesis of leukemogenesis' and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Evaluation of patients with AL or MDS'.)

CLINICAL PRESENTATION — Patients with AML generally present with symptoms related to complications of pancytopenia (eg, anemia, neutropenia, and thrombocytopenia), including weakness and easy fatigability [8], infections of variable severity, and/or hemorrhagic findings such as gingival bleeding, ecchymoses, epistaxis, or menorrhagia [9]. Combinations of these symptoms are common.

Fatigue is present in the majority of patients and often precedes the diagnosis for a number of months.

Pallor and weakness are common and attributed to the anemia.

Bone pain is infrequent in adults with AML, although some individuals 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.

It is generally difficult to precisely date the onset of AML, at least in part because individuals have different symptomatic thresholds for choosing to seek medical attention. It is likely that most patients have had more subtle evidence of bone marrow involvement for weeks, or perhaps months, before diagnosis. This can sometimes make the distinction between de novo leukemia and leukemia associated with a prior hematologic disorder such as a myelodysplastic syndrome (MDS) somewhat arbitrary. As an example, it is not uncommon for a patient to present with AML and to find evidence of a possible undiagnosed and asymptomatic MDS from blood counts obtained months to years earlier.

Fever — If fever is present, it is almost always related to infection; as such, fever should always prompt a thorough investigation of potential infectious sites and trigger immediate empiric administration of broad spectrum antibiotics if neutropenia (<1000 neutrophils/microL) is present. Whether functional neutropenia occurs in AML is less clear, but morphologic identification of hypogranular or dysplastic neutrophils in a peripheral blood smear is suggestive of such a deficit and could support the use of empiric antibiotic therapy in the absence of significant neutropenia. A small minority of patients has fever related solely to the underlying leukemia, which abates with appropriate chemotherapy; this phenomenon may be more common in patients with acute promyelocytic leukemia [10]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Skin — Examination of the skin can reveal pallor secondary to anemia, petechiae or ecchymoses secondary to thrombocytopenia or disseminated intravascular coagulation, 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. Cutaneous sites of infection may be either primary or metastatic. Rarely, cases of leukocytoclastic vasculitis have been reported [13].

The presence of erythematous to violaceous tender nodules and plaques suggests the presence of acute neutrophilic dermatosis (eg, Sweet syndrome). (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" and "Cutaneous manifestations of internal malignancy", section on 'Sweet syndrome'.)

Eyes — Careful examination of the ocular fundus reveals hemorrhages and/or whitish plaques in most patients. The conjunctivae may be pale, according to the magnitude of the anemia, although the sensitivity and clinical value of this finding are highly variable [14]. (See "Acute myeloid leukemia: Overview of complications", section on 'Ocular involvement'.)

Central nervous system — The incidence of central nervous system (CNS) involvement at the time of diagnosis is unknown since routine evaluation in patients without signs or symptoms is not recommended. Clinically overt CNS involvement developing throughout the entire course of treatment is uncommon, perhaps related to the administration of high dose cytarabine as post-remission therapy [15]. CNS involvement may be more common in patients with AML with a prominent monocytic component (eg, acute monocytic leukemia or acute myelomonocytic leukemia), hyperleukocytosis, and patients under two years of age [16,17]. Marked elevations of lactate dehydrogenase (LDH) and abnormalities of chromosomes 11 and 16 have also been associated with CNS disease at presentation or relapse [18]. Patients with CNS involvement may be asymptomatic or complain of headache, cranial nerve palsies, or visual changes. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

Oropharynx — Careful examination of the oropharynx and teeth may reveal leukemic involvement (eg, gingival hypertrophy, especially in the monocytic subtypes (picture 2) [19]), oral candidiasis, or herpetic lesions. A dental examination should be included in the pretreatment evaluation so that effective dental prophylaxis (eg, extractions) can be performed, if time and blood counts permit, prior to beginning chemotherapy [20].

Organomegaly — Palpable adenopathy is uncommon in patients with AML and significant lymph node enlargement is rare. Similarly, hepatomegaly and splenomegaly are present in approximately 10 percent of cases each and, if found, may suggest the possibility of acute lymphoblastic leukemia or evolution of AML from a prior myeloproliferative disorder (eg, blast crisis of chronic myeloid leukemia) [21].

Joints — Approximately 4 percent of patients with AML can present with symmetric or migratory polyarthritis/arthralgia as well as bone pain and tenderness. However, multiple causes of joint disease might be present in an AML patient, particularly when one or more joints are involved. These might include 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".)

Myeloid sarcoma — Less than 1 percent of patients will present with prominent extramedullary disease (ie, myeloid sarcoma, also called granulocytic sarcoma, myeloblastoma, or chloroma) [5]. Extramedullary disease may present simultaneously with or precede bone marrow disease, and may be seen in relapse. When found in association with blood or bone marrow involvement, it occurs most commonly as either cutaneous or gingival infiltration by leukemic cells, and is most often seen when there is a prominent monocytic component to the leukemia (eg, in acute monocytic or monoblastic leukemia or in acute myelomonocytic leukemia).

Sites of isolated myeloid sarcoma include bone, periosteum, soft tissues, and lymph nodes, and less commonly the orbit, intestine, mediastinum, epidural region, uterus, and ovary [22-28]. Myeloid sarcoma should always be considered in the differential diagnosis of a "small round blue cell tumor," and should be more seriously suspected if eosinophilic myelocytes are seen on hematoxylin and eosin-stained biopsies. The definitive diagnosis rests on identifying the tumor cells as myeloid with the use of myeloperoxidase or lysozyme staining, flow cytometry, or immunophenotyping from tissue sections [22,25]. (See 'Diagnosis' below.)

Differential diagnostic considerations for myeloid sarcoma include extramedullary blast crisis of chronic myeloid leukemia, or the acute leukemic transformations of other chronic disorders such as myeloproliferative neoplasms, particularly primary myelofibrosis. Careful review of the patient's history and correlation with other findings in the blood and bone marrow will make these apparent.

It is important to note that the approach to treatment of patients with myeloid sarcoma without evidence of AML on bone marrow biopsy is similar to that for patients with overt AML [12,29]. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

METABOLIC AND ELECTROLYTE ABNORMALITIES — Patients with AML can present with a wide range of metabolic and electrolyte abnormalities, many of which are due to a high turnover of the proliferating leukemic cells. Importantly, 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. In addition, the presence of high numbers of metabolically active circulating white cells can interfere with certain laboratory tests. This can result in spuriously high potassium and decreased serum glucose. Hypoxemia in an arterial blood gas may be seen with normal arterial oxygen saturation levels [30]. Metabolic abnormalities in AML are described in more detail separately. (See "Acute myeloid leukemia: Overview of complications", section on 'Metabolic abnormalities'.)

PATHOLOGIC FEATURES

Peripheral blood — Analysis of the peripheral blood at presentation usually reveals a normocytic, normochromic anemia that can vary in severity. The reticulocyte count is normal or decreased. Approximately 75 percent of patients have platelet counts below 100,000 cells/microL (100 x 109/L) at diagnosis, and approximately 25 percent will have counts below 25,000 cells/microL. Both morphologic and functional platelet abnormalities may be seen.

The median leukocyte count at diagnosis is approximately 15,000 cells/microL; 20 percent of patients have a leukocyte count above 100,000 cells/microL and 25 to 40 percent of patients have a leukocyte count less than 5000 cells/microL. The vast majority of patients (95 percent) will have circulating myeloblasts that can be detected on the peripheral smear. There may or may not be evidence of myelodysplasia. Myeloblasts can be detected by automated cell counters; they are typically reported as "Other" and are referred for review by the technical staff or a hematopathologist.

Myeloblasts are immature cells with large nuclei, usually with prominent nucleoli, and a variable amount of pale blue cytoplasm (sometimes with faint granulation) after staining with Wright Giemsa. The nuclear to cytoplasmic ratio and morphology vary depending upon the maturity of the cell. Auer rods, which are pathognomonic of myeloblasts, vary in frequency depending upon the AML subtype. They can be identified as pink/red rod-like granular structures in the cytoplasm (picture 3). Sometimes the Auer rods are multiple, and sometimes they form a dense clump and are referred to as "Auer bodies."

A myeloperoxidase reaction is easy to perform, can be done in less than a few minutes, and is a simple means of determining if the blasts are myeloid. Absence of a reaction product does not rule out AML, as some cases are negative. Evaluation of myeloperoxidase reactivity must be focused on the blast population and not on mature or maturing myeloid elements on the smear. Some blasts are strongly positive in the reaction, but some can be extremely weak developing only a tiny focus of the reaction product. Some cases can have only a small proportion of the blasts showing the reaction product. (See "Acute myeloid leukemia: Classification", section on 'AML with defining genetic abnormalities'.)

Flow cytometry of the peripheral blood or marrow aspirate can identify circulating myeloblasts in the majority of patients by characteristic patterns of surface antigen expression (table 1) [31]. The specific pattern differs among the AML subtypes, but the majority of cases express CD34, HLA-DR, CD117, CD13, and CD33. Myeloblasts may express T or B cell antigens, most commonly in cytogenetically defined subtypes of AML (eg, CD19 expression in AML with RUNX1-RUNX1T1, CD2 expression in acute promyelocytic leukemia [APL]) and in acute leukemias of ambiguous lineage (mixed phenotype acute leukemia [MPAL]). Care must be taken in interpreting the antigen profile, and in distinguishing AML from ALL or MPAL [32]. In general, the panel of antigens analyzed must contain multiple myeloid, B and T cell markers; the presence of a single B or T cell marker (eg, CD19 or CD7) is insufficient for diagnosing MPAL.

Bone marrow biopsy and aspirate

Blast count — Bone marrow aspiration and biopsy (usually unilateral) is a key component to the diagnosis of AML. The bone marrow is usually hypercellular due to a partial or almost total replacement of the normal cellular components of the marrow by immature or undifferentiated cells, although AML can sometimes present with a hypocellular marrow.

The bone marrow biopsy gives a general overview of the degree of involvement and specific histologic features associated with the process (eg, fibrosis, necrosis). The aspirate provides material for a 500-cell differential count to determine the percentage of blasts in the marrow; it also provides for detailed cytologic evaluation of the blasts and other cells that may be residual normal hematopoietic elements or abnormal cells maturing from the blasts. The differential count from the morphologic evaluation of the aspirate is critical; flow cytometry is not reliable for estimating the blast percentage because it may be influenced by hemodilution, specimen preparation (eg, red cell lysis technique, density gradient centrifugation), and gating criteria for different cell populations.

Cell origin — The blasts in AML must be identified as cells of the myeloid, monocytic, erythroid, or megakaryocytic lineage and are distinguished from blasts of the lymphoid lineage seen in acute lymphoblastic leukemia. The non-lymphoid lineage of the AML blasts can be identified by any of the following:

The presence of an Auer rod on microscopy (picture 3).

Cytochemical studies demonstrating positivity for Sudan black B, myeloperoxidase, chloroacetate esterase, or nonspecific esterase (table 1) [33].

Flow cytometry identifying the expression of myeloid antigens. It is notable that up to 20 percent of acute myeloid leukemias will demonstrate coexpression of lymphoid markers (eg, CD7, CD19, CD2). The outcome after treatment with AML directed therapy is not affected by the coexpression of "lymphoid" antigens. "True" MPAL is very uncommon and the diagnosis requires coexpression of unambiguous myeloid markers and the presence of lymphoid markers for B lineage. (See 'Differential diagnosis' below.)

Specific cytogenetic abnormalities that are seen only in myeloid leukemias.

Many hospital and commercial laboratories perform next-generation sequencing (NGS) on a panel of genes that are commonly mutated in AML ("myeloid gene panel") [34]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Other informative techniques that are not routinely applied in the clinical setting are gene expression profiling (GEP), proteomics, and expression of regulatory microRNAs (miRNA) [35]. (See "Tools for genetics and genomics: Gene expression profiling".)

Bone marrow infiltration — The bone marrow biopsy of patients with AML is infiltrated with a monotonous leukemic (blast) population. Blasts include myeloblasts, monoblasts, promonocytes, abnormal promyelocytes, and megakaryoblasts. Pronormoblasts are blast equivalents only in pure erythroid leukemia. In the current World Health Organization classification system, blast forms must account for at least 20 percent of the total cellularity [36,37]. In addition, the presence of these genetic abnormalities are considered diagnostic of AML without regard to the blast count:

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

APL with t(15;17)(q24.1;q21.1); PML-RARA

It should be noted that the older French, American, and British (FAB) classification system used a blast percent cutoff value of 30 percent to define AML. The presence of a myeloid sarcoma is also diagnostic of AML, independent of the blast count.

Cytogenetic features — All patients with suspected AML should undergo metaphase cytogenetic analysis of their bone marrow biopsy specimen. Approximately 50 percent of patients with newly diagnosed AML will demonstrate cytogenetic abnormalities.

A combination of conventional karyotypic analysis plus reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH) for specific abnormalities can aid in the diagnosis, treatment, and post-treatment monitoring of patients with AML:

Certain AML subtypes are defined by recurrent cytogenetic abnormalities (table 2). (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Acute myeloid leukemia: Classification", section on 'AML with defining genetic abnormalities'.)

Karyotype is one of the main determinants of prognosis in AML and is often used to choose the appropriate post-remission therapy. (See "Acute myeloid leukemia in younger adults: Post-remission therapy" and "Acute myeloid leukemia: Risk factors and prognosis" and "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Prognosis'.)

FISH analysis for the more prevalent karyotypic abnormalities, including t(8;21)(q22;q22), RUNX1-RUNX1T1; inv(16)(p13.1q22), t(16;16)(p13.1;q22), CBFB-MYH11; t(15;17)(q24.1;q21.1), PML-RARA, BCR-ABL1, and abnormalities of chromosomes 11q23, 3, 5, 7, and 8 can complement cytogenetic findings. FISH for t(15;17) can be completed rapidly when a diagnosis of APL (PML-RARA) needs to be excluded. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

Identified cytogenetic abnormalities can also be used to monitor for measurable residual disease (MRD; also referred to as minimal residual disease) after treatment if a RT-PCR or FISH probe is available for the abnormality. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

Molecular studies — Abnormalities in certain genes, such as mutations in FLT3, nucleophosmin (NPM1), KIT, CEBPA, IDH1 and IDH2, p53, or RUNX1 as well as gene expression profiles confer prognostic significance in adult patients with AML. AML with mutations of NPM1, RUNX1, biallelic CEBPA, PML-RARA, and others are included as specific entities in the World Health Organization classification (table 2) [37]. Patients with newly diagnosed AML should have molecular genetic factors analyzed promptly because they may influence the selection of induction and post-remission therapy and they have prognostic significance. (See "Acute myeloid leukemia: Classification", section on 'AML with defining genetic abnormalities'.)

DIAGNOSIS

Evaluation — Evaluation of patients presenting with a presumptive diagnosis of acute leukemia should be performed according to College of American Pathologists and the American Society of Hematology (CAP-ASH) guidelines [38]. Although a presumptive diagnosis of AML can be made via examination of the peripheral blood smear when there are circulating leukemic blasts, a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy. Occasional patients may have a "dry tap" on aspiration, due to the presence of a hypercellular marrow packed with blasts, or extensive fibrosis. An adequate bone marrow biopsy with touch preparations should provide sufficient material for diagnostic purposes in situations when the marrow cannot be aspirated. A portion of the biopsy can be submitted in saline or preferably culture medium (eg, Roswell Park Memorial Institute culture medium, RPMI) and crushed in the flow cytometry laboratory in an attempt to isolate a blast cell suspension for analysis. Bone marrow necrosis may be seen in highly aggressive AML variants. If excessive necrosis is present, the diagnosis must be made from the findings in the peripheral blood or if inadequate for diagnosis, another bone marrow biopsy site must be considered. (See "Evaluation of bone marrow aspirate smears", section on 'Sample preparation'.)

Despite the presence of neutropenia, thrombocytopenia, and/or coagulopathy, it is unusual to have bleeding or infection develop at the site of marrow aspiration/biopsy as a complication of the procedure. The preferred biopsy location in adults is the posterior superior iliac crest, although a different site should be used if the patient has received prior irradiation to this area. The sternum is a reasonable alternative site for bone marrow aspiration, although bone marrow biopsy cannot be performed at this site. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Choice of aspiration or biopsy site'.)

It is important that the laboratory be notified at the time of the procedure, as multiple studies need to be performed on the freshly-obtained specimen. Appropriate handling of the specimen includes:

Preparation of multiple marrow aspirate smears for Wright or Wright-Giemsa staining (used for subsequent differential count), and for additional cytochemical reactions (eg, myeloperoxidase reaction and non-specific esterase reactions). Iron staining is also performed on a marrow aspirate smear and could be useful for the identification of ring sideroblasts in AML with myelodysplastic features.

Submission of the biopsy for appropriate fixation, decalcification, and tissue sectioning, and for subsequent staining with hematoxylin and eosin, reticulin, and for additional immunohistochemical or cytochemical stains, if required.

Submission of marrow aspirate for cytogenetic and molecular genetic analysis.

Submission of the marrow aspirate for flow cytometric analysis. Alternatively, the blood could be used for flow cytometry if there are sufficient blasts in the circulation for phenotyping.

Submission of the aspirate for cultures, which should be done only if there is suspicion of infection caused by mycobacteria, yeast, or fungi.

Morphologic, immunophenotypic, cytogenetic, and molecular genetic studies must be performed in every case; cytochemical stains (optional) may be useful when rapid distinction of AML from other histologies is needed. Information derived from these studies is required for the correct diagnosis and appropriate World Health Organization classification (table 2). The selection of treatment modality and an accurate prognosis are strongly dependent upon information derived from these studies.

Diagnosis — The diagnosis of AML requires both of the following:

Documentation of bone marrow infiltration – Blast forms must account for at least 20 percent of the total cells of the bone marrow aspirate (from a 500-cell differential count). Whether or not a blast percentage can be determined in the bone marrow, the presence of 20 percent or more blasts in the peripheral blood is also diagnostic of AML. Exceptions to this include leukemias with certain genetic abnormalities, such as those with t(8;21), inv(16), or t(15;17), and myeloid sarcoma, which are considered diagnostic of AML without regard to the blast count. (See 'Bone marrow infiltration' above and "Acute myeloid leukemia: Classification".)

The leukemic cells must be of myeloid origin as demonstrated by either the presence of Auer rods, cytochemical positivity for myeloperoxidase, or presence of sufficient myeloid/monocytic markers recognized by immunophenotyping. (See 'Cell origin' above.)

DIFFERENTIAL DIAGNOSIS — Entities in the differential diagnosis of AML include those where:

The blast count is borderline at approximately 20 percent (eg, in myelodysplastic or myelodysplastic/myeloproliferative syndromes); blasts can be elevated in regenerating bone marrow after chemotherapy or those altered by growth factor effect.

The blasts are difficult to demonstrate as being myeloid – Examples include acute lymphoblastic leukemia with coexpression of myeloid markers, mixed phenotype acute leukemias, and in non-hematopoietic tumors (perhaps most commonly small cell carcinomas of the lung where the characterization of the cells infiltrating the marrow can be dependent on immunophenotyping using antibodies specific for solid tumors).

Erythroid elements are prominent and mimic erythroleukemia (eg, vitamin B12 and folate deficiency).

There are 20 percent or more blasts that are clearly myeloblasts but which actually represent transformations of other chronic myeloid disorders (eg, chronic myeloid leukemia in blast crisis, or myeloproliferative, myelodysplastic, or overlap myelodysplastic/myeloproliferative neoplasms transforming to AML).

It is critical to distinguish AML from chronic myeloid leukemia (CML) in blast crisis due to the importance of tyrosine kinase inhibitors in the treatment of the latter. AML transforming from myelodysplastic syndrome is still considered AML, but in those transforming from other myeloproliferative or myelodysplastic/myeloproliferative neoplasms, it is useful to know that the acute disease arose from an underlying chronic entity.

WHO CLASSIFICATION — Following diagnosis, AML should be classified into the appropriate subtype, according to the current World Health Organization (WHO) classification scheme (table 2). The subtype is important to help select appropriate therapy in some instances, to provide prognostic information, and in the future to help clarify underlying molecular pathogenesis so that improved therapies might be developed. This is discussed in more detail 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 5th to 6th 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 10th to 12th 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

Definition – Acute myeloid leukemia (AML; formerly called acute myelogenous leukemia) refers to a diverse group of aggressive hematologic malignancies involving proliferation of myeloid blasts committed to the granulocytic, monocytic, erythroid, or megakaryocytic lineages (table 2).

Epidemiology – AML accounts for 80 percent of acute leukemias in adults; the median age at diagnosis is 65 years. By contrast, AML represents <10 percent of acute leukemias in children <10 years. (See 'Epidemiology' above.)

Presentation – Patients generally present with symptoms of fatigue, dyspnea, fever, infections, bleeding, or bruising due to cytopenias. Less commonly, patients present with respiratory or neurological symptoms due to leukostasis, cutaneous or other extramedullary collections of leukemic blasts (chloroma), or metabolic complications of AML. Some patients are asymptomatic and are first detected by abnormal laboratory studies. (See 'Clinical presentation' above.)

Evaluation

Complete blood count (CBC) – CBC usually reveals leukocytosis due to malignant blasts, but the leukocyte count may be low or normal with few or no blasts are detected; most patients have a normochromic, normocytic anemia and thrombocytopenia. (See 'Peripheral blood' above.)

Blood smear – Myeloblasts characteristically appear as immature cells with large nuclei, prominent nucleoli, variable amounts of cytoplasm, faint granulation, and may have Auer rods (picture 3) with Wright Giemsa staining. The microscopic appearance of blasts can vary with the category of AML.

Bone marrow (BM) examination – BM is generally hypercellular with ≥20 percent blasts and replacement of normal, maturing cells. There may be substantial fibrosis in some cases.

Diagnosis – AML is generally diagnosed by morphologic, cytochemical, immunophenotypic, and cytogenetic/molecular analysis of bone marrow; in some cases, AML can be diagnosed from blood or a chloroma. (See 'Diagnosis' above.)

Criteria for the diagnosis of AML include:

Diagnostic cytogenetic/molecular features – The following cytogenetic/molecular features are sufficient to diagnose AML:

-AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

-AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

-APL with t(15;17)(q24.1;q21.1); PML-RARA

Myeloid sarcoma – A tumor mass of myeloid blasts that effaces normal tissue architecture at a site outside of the BM.

Others – In the absence of the features listed above, the diagnosis of AML requires (see 'Diagnosis' above):

-Blasts – ≥20 percent blasts in bone marrow or blood

-Myeloid immunophenotype – Documentation of myeloid lineage of blasts by flow cytometry and/or immunohistochemistry

Classification – AML should be classified according to the World Health Organization (WHO) classification scheme (table 2), as described separately. (See "Acute myeloid leukemia: Classification".)

Differential diagnosis – AML must be distinguished other bone marrow failure states (eg, aplastic anemia, nutritional deficiencies, myelofibrosis) and from lymphoid leukemia, chronic myeloid leukemia, myelodysplastic syndromes (MDS), and a leukemoid reaction (non-malignant leukocytosis due to an extreme response to infection). (See 'Differential diagnosis' above.)

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

  1. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control 2008; 19:379.
  2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67:7.
  3. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116:3724.
  4. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 2011; 105:1684.
  5. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 2012; 119:34.
  6. https://seer.cancer.gov/csr/1975_2014/browse_csr.php?sectionSEL=13&pageSEL=sect_13_table.13.html (Accessed on June 07, 2017).
  7. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10.
  8. Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 2005; 104:788.
  9. Nebgen DR, Rhodes HE, Hartman C, et al. Abnormal Uterine Bleeding as the Presenting Symptom of Hematologic Cancer. Obstet Gynecol 2016; 128:357.
  10. Daly PA, Schiffer CA, Wiernik PH. Acute promyelocytic leukemia--clinical management of 15 patients. Am J Hematol 1980; 8:347.
  11. Ratnam KV, Khor CJ, Su WP. Leukemia cutis. Dermatol Clin 1994; 12:419.
  12. Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. Blood 2011; 118:3785.
  13. Desai A, Desai A, Staszewski H, Cunha BA. An unusual initial manifestation of acute leukemia. Am J Med 2012; 125:1173.
  14. Karesh JW, Goldman EJ, Reck K, et al. A prospective ophthalmic evaluation of patients with acute myeloid leukemia: correlation of ocular and hematologic findings. J Clin Oncol 1989; 7:1528.
  15. Castagnola C, Nozza A, Corso A, Bernasconi C. The value of combination therapy in adult acute myeloid leukemia with central nervous system involvement. Haematologica 1997; 82:577.
  16. Cassileth PA, Sylvester LS, Bennett JM, Begg CB. High peripheral blast count in adult acute myelogenous leukemia is a primary risk factor for CNS leukemia. J Clin Oncol 1988; 6:495.
  17. Dekker AW, Elderson A, Punt K, Sixma JJ. Meningeal involvement in patients with acute nonlymphocytic leukemia. Incidence, management, and predictive factors. Cancer 1985; 56:2078.
  18. Shihadeh F, Reed V, Faderl S, et al. Cytogenetic profile of patients with acute myeloid leukemia and central nervous system disease. Cancer 2012; 118:112.
  19. Blum W, Mrózek K, Ruppert AS, et al. Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature. Cancer 2004; 101:1420.
  20. Williford SK, Salisbury PL 3rd, Peacock JE Jr, et al. The safety of dental extractions in patients with hematologic malignancies. J Clin Oncol 1989; 7:798.
  21. Byrd JC, Mrózek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100:4325.
  22. Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 2002; 94:1739.
  23. Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995; 13:1800.
  24. Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981; 48:1426.
  25. Paydas S, Zorludemir S, Ergin M. Granulocytic sarcoma: 32 cases and review of the literature. Leuk Lymphoma 2006; 47:2527.
  26. Choi EK, Ha HK, Park SH, et al. Granulocytic sarcoma of bowel: CT findings. Radiology 2007; 243:752.
  27. Seok JH, Park J, Kim SK, et al. Granulocytic sarcoma of the spine: MRI and clinical review. AJR Am J Roentgenol 2010; 194:485.
  28. Shinagare AB, Krajewski KM, Hornick JL, et al. MRI for evaluation of myeloid sarcoma in adults: a single-institution 10-year experience. AJR Am J Roentgenol 2012; 199:1193.
  29. Tsimberidou AM, Kantarjian HM, Wen S, et al. Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia. Cancer 2008; 113:1370.
  30. Mizock BA, Franklin C, Lindesmith P, Shah PC. Confirmation of spurious hypoxemia using continuous blood gas analysis in a patient with chronic myelogenous leukemia. Leuk Res 1995; 19:1001.
  31. Kaleem Z, Crawford E, Pathan MH, et al. Flow cytometric analysis of acute leukemias. Diagnostic utility and critical analysis of data. Arch Pathol Lab Med 2003; 127:42.
  32. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008; 111:3941.
  33. Baer MR, Stewart CC, Dodge RK, et al. High frequency of immunophenotype changes in acute myeloid leukemia at relapse: implications for residual disease detection (Cancer and Leukemia Group B Study 8361). Blood 2001; 97:3574.
  34. Haferlach T, Kohlmann A, Wieczorek L, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol 2010; 28:2529.
  35. Yendamuri S, Calin GA. The role of microRNA in human leukemia: a review. Leukemia 2009; 23:1257.
  36. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  37. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  38. Arber DA, Borowitz MJ, Cessna M, et al. Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med 2017; 141:1342.
Topic 4497 Version 43.0

References

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