INTRODUCTION Acute myeloid leukemia (AML, also known as acute myelogenous leukemia) consists of a

group of relatively well-defined hematopoietic neoplasms involving precursor cells committed to the myeloid
line of cellular development (ie, those giving rise to granulocytic, monocytic, erythroid, or megakaryocytic
elements).
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.
EPIDEMIOLOGY AML is the most common acute leukemia in adults and accounts for approximately 80
percent of cases in this group [1,2]. In the United States and Europe, the incidence has been stable at 3 to 5
cases per 100,000 population [3-5]. In contrast, AML accounts for less than 10 percent of acute leukemias in
children less than 10 years of age.
In adults, the median age at diagnosis is approximately 65 years. The incidence increases with age with
approximately 1.3 and 12.2 cases per 100,000 population for those under or over 65 years, respectively. The
male:female ratio is approximately 5:3. This incidence is similar among persons of different races. In one study,
non-Hispanic whites had the highest incidence (four cases per 100,000 population), while Hispanic whites,
blacks, and Asian Pacific Islanders had a slightly lower incidence (three cases per 100,000 population).
AML has been associated with environmental factors (eg, exposure to chemicals, radiation, tobacco, or
chemotherapy drugs), genetic abnormalities (eg, trisomy 21, Fanconi's anemia, Bloom's syndrome, familial
RUNX1 mutations), and other benign (eg, paroxysmal nocturnal hemoglobinuria, aplastic anemia) and
malignant (eg, myelodysplastic syndrome and myeloproliferative disorders) hematologic diseases.
CLINICAL PRESENTATION Patients with AML generally present with symptoms related to complications of
pancytopenia (eg, anemia, neutropenia, and thrombocytopenia), including weakness and easy fatigability [7],
infections of variable severity, and/orhemorrhagic findings such as gingival bleeding, ecchymoses, epistaxis, or
menorrhagia [8]. Combinations of these symptoms are common.
General 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 (<1000neutrophils/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 [9].
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) [10,11]. 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
[12].
The presence of erythematous to violaceous tender nodules and plaques suggests the presence of acute
neutrophilic dermatosis (eg, 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.
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 [13]. 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 [14,15]. Marked elevations
of the LDH and abnormalities of chromosomes 11 and 16 have also been associated with CNS disease at
presentation or relapse [16]. Patients with CNS involvement may be asymptomatic or complain of headache,
cranial nerve palsies, or visual changes.
Oropharynx Careful examination of the oropharynx and teeth may reveal leukemic involvement (eg,
gingival hypertrophy, especially in the monocytic subtypes (picture 2) [17]), 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 [18].
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) [19].
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.
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 [20-26]. 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 [20,23].
Differential diagnostic considerations for myeloid sarcoma include extramedullary blast crisis of chronic
myeloid leukemia (CML), 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 [11,27].
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.
Other metabolic derangements that are 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 [28]. Metabolic abnormalities in
AML are described in more detail separately.
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 x 109/L (100,000/microL) at diagnosis, and approximately
25 percent will have counts below 25 x 109/L (25,000/microL). Both morphologic and functional platelet
abnormalities may be seen.
The median leukocyte count at diagnosis is approximately 15 x 109/L (15,000 cells/microL); 20 percent of
patients have a leukocyte count above 100 x 109/L (100,000 cells/microL) and 25 to 40 percent of patients
have a leukocyte count less than 5 x 109/L (5000cells/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 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 (table 1). 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.
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 2) [29]. 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 APL) and in acute leukemias of
ambiguous lineage (mixed phenotype acute leukemia, or MPAL). Care must be taken in interpreting the
antigen profile, and in distinguishing AML from ALL or MPAL [30]. 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 usually insufficient for diagnosing a 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 aspirate is critical because the blast percentage from the flow
specimen may be influenced by hemodilution and artifacts produced by the variability by which the specimen is
prepared (eg, red cell lysis techniques, density gradient centrifugation) and the approach through which
different cell populations are selected for gating.
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 (ALL). 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 and table 2) [31].
Flow cytometry identifying the expression of myeloid antigens. It is notable that up to 20 percent of acute
myeloid leukemias will demonstrate co-expression of lymphoid markers (eg, CD7, CD19, CD2). The

outcome after treatment with AML directed therapy is not affected by the co-expression of lymphoid
antigens. True mixed phenotype acute leukemia (MPAL) is very uncommon and the diagnosis requires
co-expression of unambiguous myeloid markers and the presence of lymphoid markers for B lineage.
Specific cytogenetic abnormalities that are seen only in myeloid leukemias (eg, t(1;22)(p13;q13)).
Evolving techniques include proteomics and gene expression profiling (GEP) (figure 1). GEP in particular has
shown great promise for diagnosis, classification, and prognosis in AML [32]. Expression of regulatory
microRNAs (miRNA) is being increasingly recognized as an important prognostic tool [33]. This is discussed in
more detail separately.
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
WHO classification system, blast forms must account for at least 20 percent of the total cellularity [34,35]. 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
The presence of a myeloid sarcoma is also diagnostic of AML independent of the blast count. Of note, the
previous French, American, and British (FAB) classification system used a blast percent cutoff value of 30
percent to define AML. Patients with blast counts between 20 and 30 percent had previously been classified as
refractory anemia with excess blasts in transformation (RAEB-T).
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 (RTPCR) 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 3).
Karyotype is one of the main determinants of prognosis in AML and is often used to choose the
appropriate post-remission therapy.
FISH analysis for the more prevalent karyotypic abnormalities, including t(8;21)(q22;q22), RUNX1RUNX1T1; 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.
Identified cytogenetic abnormalities can also be used to monitor for minimal residual disease after
treatment if a RT-PCR or FISH probe is available for the abnormality.
Molecular studies Abnormalities in certain genes, such as mutations in FLT3, nucleophosmin (NPM1), KIT,
CEBPA, or RUNX1 as well as gene expression profiles confer prognostic significance in adult patients with
AML. AML with NPM1 or biallelic CEBPA mutations are included as specific entities in the WHO classification
[35]. AML with mutated RUNX1 is included as a provisional entity. Patients with newly diagnosed AML,

particularly younger patients, should have these molecular genetic factors analyzed because they have
prognostic importance, already have therapeutic implications with respect to post-remission therapy choices
(transplant versus chemotherapy), and might become targets of agents undergoing development and study
[36].
DIAGNOSIS
Evaluation 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.
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 and spine, 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.
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, cytochemical or immunophenotypic, and cytogenetic and molecular studies must be performed in
every case. Information derived from these studies is important for the correct diagnosis, and also for the
subclassification of the process. 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. In addition, acute promyelocytic leukemia and acute erythroleukemia
have different diagnostic criteria "Classification of acute myeloid leukemia".)
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 markers recognized by
immunophenotyping
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/myeloproliferativesyndromes); 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 (ALL) with co-expression of myeloid markers, mixed phenotype acute leukemias, and in nonhematopoietic 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 overlapmyelodysplastic/myeloproliferative neoplasms transforming
to AML).
While up to 20 percent of acute myeloid leukemias will demonstrate co-expression of lymphoid markers (eg,
CD7, CD19, CD2), the outcome after treatment with AML directed therapy is not affected by the co-expression
of "lymphoid" antigens. "True" mixed phenotype acute leukemia (MPAL) is very uncommon and the diagnosis
requires co-expression of unambiguous myeloid markers and the presence of lymphoid markers (cytoplasmic
or surface CD3 for T lineage, or CD19 with 1 or 2 of CD79A, cytoplasmic CD22 or CD10) for B lineage. The
blasts from patients with MPAL are usually morphologically undifferentiated, often lacking detectable
cytoplasmic MPO by cytochemistry or flow cytometry [37].
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
(MDS) is still considered AML, but in those transforming from other myeloproliferative
or myelodysplastic/myeloproliferative neoplasms, it may be 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. 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 "Classification of acute myeloid leukemia".)
SUMMARY
Acute leukemia should be suspected in a patient presenting with varying combinations of the following:

Signs and symptoms suggestive of anemia (eg, shortness of breath, dyspnea on exertion, pallor),
excess bleeding or bruising, and infection
A marked reduction in red cells, platelets, and mature neutrophils on a complete blood count
Accumulation of leukemic forms in the peripheral blood, bone marrow, and/or other tissues
Acute myeloid leukemia (AML) is diagnosed by bone marrow biopsy using morphologic, cytochemical,
immunophenotypic, and cytogenetic/molecular analysis (see 'Diagnosis' above):
Blast forms must account for at least 20 percent of the total cellularity of the bone marrow biopsy
sample. Exceptions to this include leukemias with certain genetic abnormalities or myeloid sarcoma,
which are considered diagnostic of AML without regard to the blast count.
The blast forms must be identified as cells of the myeloid, as distinct from the lymphoid lineage.
Following diagnosis, AML should be classified into the appropriate subtypes, according to the current
World Health Organization (WHO) classification scheme. 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.
(Charles A Schiffer, 2016)

Bibliografa
Charles A Schiffer, M. (6 de Oct de 2016). UpToDate. Recuperado el 20 de Oct de 2016, de
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