Classification of Adult Acute Myeloid Leukemia
The World Health Organization (WHO) classification of acute myeloid leukemia (AML) incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a classification that is universally applicable and prognostically valid. In the older French-American-British (FAB) criteria, the classification of AML is solely based upon morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.[2,3]
Under the WHO classification, the category “acute myeloid leukemia not otherwise categorized” is morphology-based and reflects the FAB classification with a few significant modifications.[2,3] The most significant difference between the WHO and FAB classifications is the WHO recommendation that the requisite blast percentage for the diagnosis of AML be at least 20% blasts in the blood or bone marrow. The FAB scheme required the blast percentage in the blood or bone marrow to be at least 30%. This threshold value for blast percentage eliminated the category “refractory anemia with excess blasts in transformation” (RAEB-t) found in the FAB classification of myelodysplastic syndromes (MDS), where RAEB-t is defined by a marrow blast percentage between 20% and 29%. In the WHO classification, RAEB-t is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as “AML with multilineage dysplasia following a myelodysplastic syndrome.”
Although this lowering of the blast threshold has been met with some criticism, several studies indicate that survival patterns for cases with 20% to 29% blasts are similar to survival patterns for cases with 30% or more blasts in the bone marrow.[5-9] The diagnosis of AML in itself does not represent a therapeutic mandate. The decision to treat should be based on other factors including patient age, previous history of MDS, clinical findings, disease progression, in addition to the blast percentage, and most importantly, patient preference.
Several groups have begun to investigate the use of gene expression profiling (GEP) using microarrays to augment current diagnostic and prognostic studies for AML. Distinct subsets can be identified using GEP that correspond to known cytogenetic and molecular abnormalities. The positive predictive value appears to be sufficiently powerful to be clinically useful only for patients with the t(8;21) and inv(16) (now referred to as core-binding factor [CBF] leukemias) and acute promyelocytic leukemia (APL) with the t(15;17). GEP identified several cases of CBF leukemias that were not diagnosed using conventional cytogenetics.[10-12]
In the following outline and discussion, the older FAB classifications are noted where appropriate.
- AML with characteristic genetic abnormalities.
- AML with an FLT3 mutation (not in the WHO classification scheme).
- AML with multilineage dysplasia.
- AML and MDS, therapy related.
- AML not otherwise categorized.
- Acute myeloblastic leukemia, minimally differentiated (FAB Classification M0).
- Acute myeloblastic leukemia without maturation (FAB Classification M1).
- Acute myeloblastic leukemia with maturation (FAB Classification M2).
- Acute myelomonocytic leukemia (AMML) (FAB Classification M4).
- Acute monoblastic leukemia and acute monocytic leukemia (FAB classifications M5a and M5b).
- Acute erythroid leukemias (FAB classifications M6a and M6b).
- Acute megakaryoblastic leukemia (FAB Classification M7).
- Acute basophilic leukemia.
- Acute panmyelosis with myelofibrosis.
- Myeloid sarcoma.
- Acute leukemias of ambiguous lineage.
Acute Myeloid Leukemia (AML) With Characteristic Genetic Abnormalities
This category is characterized by characteristic genetic abnormalities and frequently high rates of remission and favorable prognoses with the notable exception of those with 11q23 abnormalities. The reciprocal translocations t(8; 21), inv(16) or t(16;16), t(15; 17), and translocations involving the 11q23 breakpoint are the most commonly identified genetic abnormalities. These structural chromosome rearrangements result in the formation of fusion genes that encode chimeric proteins that may contribute to the initiation or progression of leukemogenesis. Many of these translocations are detected by reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), which has a higher sensitivity than cytogenetics. Other recurring cytogenetic abnormalities are less common and described below in AML not otherwise categorized.
Acute myeloid leukemia with t(8; 21)(q22; q22); (AML/ETO)
AML with the translocation t(8; 21)(q22; q22) (occurring most commonly in FAB classification M2) is one of the most common genetic aberrations in AML and accounts for 5% to 12% of cases of AML and 33% of karyotypically abnormal cases of acute myeloblastic leukemia with maturation. Myeloid sarcomas (chloromas) may be present and may be associated with a bone marrow blast percentage of less than 20%.
Common morphologic features include the following:
- Large blasts with abundant basophilic cytoplasm, often containing numerous azurophilic granules.
- A few blasts in some cases show very large granules (pseudo Chediak-Higashi granules).
- Auer rods, which may be detected in mature neutrophils.
- Smaller blasts, predominantly in the peripheral blood.
- Promyelocytes, myelocytes, and mature neutrophils with variable dysplasia in the bone marrow.
- Abnormal nuclear segmentation (pseudo Pelger-Huet nuclei) and/or cytoplasmic staining abnormalities.
- Increased eosinophil precursors.
- Reduced or absent monocytes.
- Normal erythroblasts and megakaryocytes.
AML with maturation (FAB classification M2) is the most common morphologic type correlating with t(8; 21). Rarely, AML with this translocation presents with a bone marrow blast percentage less than 20%.
The translocation t(8; 21)(q22; q22) involves the AML1 gene, also known as RUNX1, which encodes CBF-alpha, and the ETO (eight-twenty-one) gene.[13,15] The AML1/ETO fusion transcript is consistently detected in patients with t(8; 21) AML. This type of AML is usually associated with a good response to chemotherapy and a high complete remission (CR) rate with long-term survival when treated with high-dose cytarabine in the postremission phase as in the Cancer and Leukemia Group B (CLB-9022 and CLB-8525) trials.[16-19] Additional chromosome abnormalities are common, for example, loss of a sex chromosome and del(9)(q22). Expression of the neural-cell adhesion molecule (CD56) appears to be an adverse prognostic indicator.[20,21]
Acute myeloid leukemia with inv(16)(p13; q22) or t(16; 16)(p13; q22); (CBFβ/MYH11)
AML with inv(16)(p13; q22) or t(16; 16)(p13; q22) is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients.[13,22] Morphologically, this type of AML is associated with acute myelomonocytic leukemia (FAB classification M4) with abnormal eosinophils (AMML Eo). Myeloid sarcomas may be present at initial diagnosis or at relapse.
Common morphologic features include the following:
- Monocytic and granulocytic differentiation.
- A characteristically abnormal eosinophil component with immature purple-violet eosinophil granules that may obscure cell morphology if present in great numbers.
- Auer rods in myeloblasts.
- Decreased neutrophils in bone marrow.
Most cases with this genetic abnormality have been identified as AMML Eo, but occasional cases have been reported to lack eosinophilia. As is found in rare cases of AML with t(8; 21), the bone marrow blast percentage in this AML is occasionally less than 20%.
Both inv(16)(p13; q22) and t(16; 16)(p13; q22) result in the fusion of the CBF-beta (CBFβ) gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) gene at 16p13, thereby forming the fusion gene CBFβ/MYH11. The use of FISH and RT–PCR methods may be necessary to document this fusion gene because its presence cannot be reliably documented by traditional cytogenetics banding techniques. Patients with this type of AML may achieve higher CR rates when treated with high-dose cytarabine in the postremission phase.[16,17,19]
Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARA) and variants] (FAB Classification M3)
APL AML with t(15; 17)(q22; q12) is an AML in which promyelocytes predominate. APL exists as two types, hypergranular or typical APL and microgranular (hypogranular) APL. APL comprises 5% to 8% of cases of AML and occurs predominately in adults in midlife. Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC).[24,25] In microgranular APL, unlike typical APL, the leukocyte count is very high with a rapid doubling time.
Common morphologic features of typical APL include the following:
- Kidney-shaped or bilobed nuclei.
- Cytoplasm densely packed with large granules (bright pink, red, or purple in Romanowsky stains).
- Bundles of Auer rods within the cytoplasm (faggot cells).
- Larger Auer rods than in other types of AML.
- Strongly positive myeloperoxidase (MPO) reaction in all leukemic promyelocytes.
- Only occasional leukemic promyelocytes in the blood.
Common morphologic features of microgranular APL include the following:
- Bilobed nuclear shape.
- Apparent scarce or absent granules (submicroscopic azurophilic granules).
- Small number of abnormal promyelocytes with visible granules and/or bundles of Auer rods (faggot cells).
- High leukocyte count in the peripheral blood.
- Strongly positive MPO reaction in all leukemic promyelocytes.
In APL, the RARA) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (promyelocytic leukemia or PML gene) resulting in a PML/RARA gene fusion transcript.[14,26,27] Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARA gene into PML gene leading to the expression of the PML/RARA fusion transcript. FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.[28,29]
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent.[30-32] High CR rates in APL may be obtained by combining ATRA treatment with chemotherapy. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found in which the RARA gene is fused with other genes. Variant translocations involving the RARA gene include: t(11;17)(q23; q21), t(5;17)(q32; q12), and t(11; 17)(q13; q21).
Acute myeloid leukemia with 11q23 (MLL) abnormalities
AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This AML is more common in children. Two clinical subgroups of patients have a high frequency of AML with 11q23 abnormalities: AML in infants and therapy-related AML, usually occurring after treatment with DNA topoisomerase inhibitors. Patients may present with DIC and extramedullary monocytic sarcomas and/or tissue infiltration (gingiva, skin).
Common morphologic features of this AML include the following:
- Monoblasts and promonocytes predominate in the bone marrow.
- Monoblasts and promonocytes with strong, positive nonspecific-esterase reactions.
11q23 abnormalities are associated frequently with acute myelomonocytic, monoblastic, and monocytic leukemias (FAB classifications M4, M5a and M5b, respectively) and occasionally with AML with and without maturation (FAB classifications M2 and M1, respectively).
The MLL gene on 11q23, a developmental regulator, is involved in translocations with approximately 22 different partner chromosomes.[13,14] Genes other than MLL may be involved in 11q23 abnormalities. FISH may be required to detect genetic abnormalities involving MLL.[35-37] In general, risk categories and prognoses for individual 11q23 translocations are difficult to determine because of the lack of studies involving significant numbers of patients; however, patients with t(11; 19)(q23; p13.1) are reported to have poor outcomes.
Acute Myeloid Leukemia With Mutations of FLT3, NPM1, or CMBPA
Activating mutations of FLT3 (FMS-like tyrosine kinase-3), present at diagnosis in 20% to 30% of de novo AML, represent the most frequent molecular abnormality in this disease.[38,39] The most common type of mutation (23%) is an internal tandem duplication mutation (FLT3/ITD) localized to the juxtamembrane region of the receptor, while point mutations in the kinase domain are less common (7%). Common clinical features of patients with FLT3/ITD AML are:
- Normal cytogenetics.
- Monocytic differentiation.
Patients with FLT3/ITD mutations, and possibly those with FLT3 point mutations, are consistently reported to have an increased relapse rate and reduced overall survival (OS).[40,41] The CR rate for patients with FLT3-mutant AML is generally reported to be no different than that for patients with AML with nonmutant FLT3, but most studies examining this clinical parameter used results from patients treated with intensive chemotherapy regimens, and some data are available to suggest that the conventional 7+3 regimen leads to a reduced remission rate in this group of patients.[Level of evidence: 3iiiDiv]
One study from the German-Austrian Acute Myeloid Leukemia Study Group examined data on 872 patients with cytogenetically normal AML treated with intensive induction and postremission regimens over an 11-year period.[Level of evidence: 3iiiA] The study group found that patients with a mutant CCAAT/enhancer binding-protein alpha (CEBPA) or a nucleophosmin mutation (NPM1) without fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) had higher complete response rates, disease-free survival (DFS) rates, and OS rates (with a 4-year OS rate of 62% and 60%, respectively) than other cytogenetically normal AML patients (who had a 4-year OS rate of between 25% and 30%). As yet, no clear strategy exists for improving patient outcome in FLT3-mutant AML, or in patients with abnormalities other than CEBPA or the NPM1 without the FLT3-ITD, but small molecule FLT3 inhibitors are in development, and the role of allogeneic transplant is being considered.
Acute Myeloid Leukemia With Multilineage Dysplasia
Note: In the WHO classification, refractory anemia with excess blasts in transformation (RAEB-t) is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as one of the following:
- AML evolving from an MDS.
- AML following an MDS.
AML with multilineage dysplasia is characterized by 20% or more blasts in the blood or bone marrow and dysplasia in two or more myeloid cell lines, generally including megakaryocytes. To make the diagnosis, dysplasia must be present in 50% or more of the cells of at least two lineages and must be present in a pretreatment bone marrow specimen.[4,44] AML with multilineage dysplasia may occur de novo or following MDS or a myelodysplastic and myeloproliferative disorder (MDS and MPD). (Refer to the PDQ summaries on Myelodysplastic Syndromes Treatment/ Myelodysplastic/ Myeloproliferative Neoplasms for more information.) The diagnostic terminology “AML with multilineage dysplasia evolving from a myelodysplastic syndrome” should be used when an MDS precedes AML.
Common morphologic features include the following:
- Multilineage dysplasia in the blood or bone marrow.
- Dysplasia in 50% or more of the cells of two or more cell lines.
- Dysgranulopoiesis (neutrophils with hypogranular cytoplasm, hyposegmented nuclei or bizarrely segmented nuclei).
- Dyserythropoiesis (megaloblastic nuclei, karyorrhexis, or multinucleation of erythroid precursors and ringed sideroblasts).
- Dysmegakaryopoiesis (micromegakaryocytes and normal size or large megakaryocytes with monolobed or multiple separated nuclei).
The differential diagnosis of AML with multilineage dysplasia includes acute erythroid-myeloid leukemia and acute myeloblastic leukemia with maturation (FAB classifications M6a and M2). Some cases may overlap two morphologic types.
As evidenced in several Southwest Oncology Group studies, such as SWOG-8600 and NCT00023777, the numerous chromosome abnormalities observed in AML with multilineage dysplasia were similar to those found in MDS and frequently involved gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7.[45-48] The probability of achieving a CR has been reported to be affected adversely by a diagnosis of AML with multilineage dysplasia.[45-47]
Acute Myeloid Leukemias and Myelodysplastic Syndromes, Therapy Related
This category includes AML and MDS that arise secondary to cytotoxic chemotherapy and/or radiation therapy. The therapy-related (or secondary) MDS are included because of their close clinicopathologic relationships to therapy-related AML. Although these therapy-related disorders are distinguished by the specific mutagenic agents involved, a recent study suggests this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer.
Alkylating agent-related acute myeloid leukemia and myelodysplastic syndromes
The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years following exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months.[49,51] The risk for occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient. Clinically, the disorder commonly presents initially as an MDS with evidence of bone marrow failure. This stage is followed by dysplastic features in multiple cell lineages with a blast percentage that is usually less than 5%. In the MDS phase, approximately 66% of cases satisfy the criteria for refractory cytopenia with multilineage dysplasia (RCMD), with approximately 33% of these cases exhibiting ringed sideroblasts in excess of 15% (RCMD-RS). (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) Another 25% of cases satisfy the criteria for refractory anemia with excess blasts 1 or 2 (RAEB-1; RAEB-2). The MDS phase may evolve to a higher grade MDS or AML. Although a minority of patients may present with acute leukemia, a substantial number of patients succumb to the disorder in the MDS phase.
Common morphologic features include the following:
- Ringed sideroblasts (60% of cases; >15% in 33% of cases).
- Hypercellular bone marrow (50% of cases).
Cases may correspond morphologically to AML with maturation, acute monocytic leukemia, AMML, erythroleukemia, or acute megakaryoblastic leukemia (FAB classifications M2, M5b, M4, M6a, and M7, respectively).
Cytogenetic abnormalities have been observed in more than 90% of cases of therapy-related AML or MDS and commonly include chromosomes 5 and/or 7.[49,52,53] Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding.[50,52-54] Therapy-related AML is usually refractory to antileukemia therapy. Median survival after diagnosis of these disorders is approximately 7 to 8 months.[50,52]
Topoisomerase II inhibitor-related acute myeloid leukemia
This type of AML occurs in patients treated with topoisomerase II inhibitors. The agents implicated are the epipodophyllotoxins etoposide and teniposide and the anthracyclines doxorubicin and 4-epi-doxorubicin. The mean latency period from the time of institution of the causative therapy to the development of AML is approximately 2 years. Morphologically, there is a significant monocytic component. Most cases are categorized as acute monoblastic or myelomonocytic leukemia. Other morphologies reported include APL, myelodysplastic syndromes, and acute megakaryoblastic leukemia.
As with alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes, the cytogenetic abnormalities are often complex.[50,52-54] The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene.[50,56] Current data are insufficient to predict survival times.
Acute Myeloid Leukemia Not Otherwise Categorized
Cases of AML that do not fulfill the criteria for AML with recurrent genetic abnormalities, AML with multilineage dysplasia, or AML and MDS, therapy-related, fall within this category. Classification within this category is based on leukemic cell features of morphology, cytochemistry, and maturation.
Acute myeloblastic leukemia, minimally differentiated (FAB Classification M0)
This AML shows no evidence of myeloid differentiation by morphology and light microscopy cytochemistry. The myeloid nature of the blasts is demonstrated by immunophenotyping and/or ultrastructural studies. Immunophenotyping studies must be performed to distinguish this acute leukemia from acute lymphoblastic leukemia (ALL). AML, minimally differentiated, comprise approximately 5% of cases of AML. Patients with this AML typically present with evidence of marrow failure, thrombocytopenia, and neutropenia.
Morphologic and cytochemical features include the following:
- Medium-sized blasts with dispersed nuclear chromatin.
- Agranular cytoplasm.
- Occasionally small blasts that resemble lymphoblasts.
- Cytochemistry negative for myeloperoxidase (MPO), Sudan Black B (SBB), and naphthol ASD chloroacetate esterase (<3% positive blasts).
- Cytochemistry negative for alpha naphthyl acetate and butyrate esterases.
- Markedly hypercellular marrow.
Immunophenotyping reveals blast cells that express one or more panmyeloid antigens (CD13, CD33, and CD117) and are negative for B and T lymphoid-restricted antigens. Most cases express primitive hematopoietic-associated antigens (CD34, CD38, and HLA-DR). The differential diagnosis includes ALL, acute megakaryoblastic leukemia, biphenotypic/mixed lineage acute leukemia, and, rarely, the leukemic phase of large cell lymphoma. Immunophenotyping studies are required to distinguish these disorders.
Although no specific chromosomal abnormalities have been found in AML, minimally differentiated point mutations of the AML1 gene have been observed in approximately 25% of cases. This mutation appears to correlate clinically with a higher white blood cell count and greater marrow blast involvement.[57,59] Mutation of FLT3, a receptor tyrosine kinase gene, occurs in approximately 25% of cases and has been associated with short survival.[40,59] The median OS is approximately 10 months.
Acute myeloblastic leukemia without maturation (FAB Classification M1)
AML without maturation is characterized by a high percentage of bone marrow blasts with little evidence of maturation to mature neutrophils and comprises approximately 10% of cases of AML. Most patients are adults. Patients usually present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
Common morphologic and cytochemical features include the following:
- Myeloblasts of 90% or more of the nonerythroid cells in the bone marrow.
- Myeloblasts that may have azurophilic granules and/or Auer rods.
- Myeloblasts that resemble lymphoblasts.
- MPO and SBB positivity in blasts of 3% or more.
- Typically markedly hypercellular marrow.
Immunophenotyping reveals blasts that express at least two myelomonocytic antigens (CD13, CD33, CD117) and/or MPO. CD34 is often positive. The differential diagnosis includes ALL in cases of AML without maturation with no granules and a low percentage of MPO positive blasts, and AML with maturation in cases of AML with maturation with a high percentage of blasts.
Although no specific chromosomal abnormality has been identified for AML without maturation, mutation of the FLT3 gene has been associated with leukocytosis, a high percentage of bone marrow blast cells, and a worse prognosis.[40,57,61]
Acute myeloblastic leukemia with maturation (FAB Classification M2)
AML with maturation is characterized by 20% or more myeloblasts in the blood or bone marrow and 10% or more neutrophils at different stages of maturation. Monocytes constitute less than 20% of bone marrow cells. This AML comprises approximately 30% to 45% of cases of AML. While it occurs in all age groups, 20% of patients are younger than 25 years and 40% of patients are aged 60 years or older. Patients frequently present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
Morphologic features include the following:
- Myeloblasts with and without azurophilic granules.
- Auer rods.
- Promyelocytes, myelocytes, and neutrophils 10% or more of the bone marrow cells.
- Abnormal nuclear segmentation in neutrophils.
- Increased eosinophil precursors (frequently).
- Hypercellular marrow (usually).
- Blasts and maturing neutrophils reactive with antibodies to MPO and lysozyme.
With immunophenotyping, the blasts typically express one or more myeloid-associated antigens (CD13, CD33, and CD15). The differential diagnosis includes: RAEB in cases with a low blast percentage, AML without maturation when the blast percentage is high, and AMML in cases with increased monocytes.
Approximately 33% of karyotypically abnormal cases of AML with maturation are associated with t(8; 21)(q22;q22). (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) Such cases have a favorable prognosis. Rare cases with t(6; 9)(q23; q34) are reported to have a poor prognosis.[57,62]
Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARA) and variants] (FAB Classification M3)
(Refer to the Acute promyelocytic leukemia (FAB Classification M3) section of the Acute Myeloid Leukemia With Characteristic Genetic Abnormalities section of this summary for more information.)
Acute myelomonocytic leukemia (FAB Classification M4)
Acute myelomonocytic leukemia (AMML) is characterized by the proliferation of neutrophil and monocyte precursors. Patients usually present with anemia and thrombocytopenia. (Refer to the PDQ summary on Fatigue for more information on anemia.) This classification of AML comprises approximately 15% to 25% of cases of AML, and some patients have a previous history of chronic myelomonocytic leukemia (CMML). (Refer to the PDQ summary on Myelodysplastic/ Myeloproliferative Neoplasms for more information.) This type of AML occurs more commonly in older individuals.
Morphologic and cytochemical features include the following:
- 20% or more blasts in the bone marrow.
- 20% or more neutrophils, monocytes, and their precursors in the bone marrow (to distinguish AMML from AML with or without maturation and to increase monocytes).
- 5 x 109/L or more monocytes in the blood.
- Large monoblasts with round nuclei, abundant cytoplasm, and prominent nucleoli.
- MPO positivity in at least 3% of blasts.
- Monoblasts, promonocytes, and monocytes typically nonspecific esterase (NSE)-positive.
Immunophenotyping generally reveals monocytic differentiation markers (CD14, CD4, CD11b, CD11c, CD64, and CD36) and lysozyme. The differential diagnosis includes AML with maturation and acute monocytic leukemia.
Most cases of AMML exhibit nonspecific cytogenetic abnormalities. Some cases may have a 11q23 genetic abnormality. Cases with increased abnormal eosinophils in the bone marrow associated with a chromosome 16 abnormality have a favorable prognosis. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.)
Acute monoblastic leukemia and acute monocytic leukemia (FAB classifications M5a and M5b)
Acute monoblastic and acute monocytic leukemia are AMLs in which 80% or more of the leukemic cells are of a monocytic lineage. These cells include monoblasts, promonocytes, and monocytes. These two leukemias are distinguished by the relative proportions of monoblasts and promonocytes. In acute monoblastic leukemia, most monocytic cells are monoblasts (usually ≥80%). In acute monocytic leukemia, most of the monocytic cells are promonocytes. Acute monoblastic leukemia comprises 5% to 8% of cases of AML and occurs most commonly in young individuals. Acute monocytic leukemia comprises 3% to 6% of cases and is more common in adults. Common clinical features for both acute leukemias include bleeding disorders, extramedullary masses, cutaneous and gingival infiltration, and central nervous system involvement.
Morphologic and cytochemical features of acute monoblastic leukemia include the following:
- Large basophilic monoblasts with abundant cytoplasm, pseudopod formation, round nuclei, and one or more prominent nucleoli.
- Rare Auer rods.
- Typically intensely NSE-positive and MPO-negative.
- Hypercellular marrow with large numbers of monoblasts.
- Lysozyme positive.
Morphologic and cytochemical features of acute monocytic leukemia include the following:
- Promonocytes with an irregular nuclear configuration with a moderately basophilic cytoplasm and cytoplasmic azurophilic granules.
- Typically intensely NSE-positive.
- Occasional MPO positivity.
- Hemophagocytosis (erythrophagocytosis).
The extramedullary lesions of these leukemias may be predominantly monoblastic or monocytic or an admixture of the two cell types. Immunophenotyping of these leukemias may reveal expression of the myeloid antigens CD13, CD33, CD117, CD14 ( + ), CD4, CD36, CD 11b, CD11c, CD64, and CD68. The differential diagnosis of acute monoblastic leukemia includes AML without maturation, minimally differentiated AML, and acute megakaryoblastic leukemia. The differential diagnosis of acute monocytic leukemia includes AMML and microgranular APL.
An abnormal karyotype has been observed in approximately 75% of cases of acute monoblastic leukemia while approximately 30% of cases of acute monocytic leukemia are associated with an abnormal karyotype. Almost 30% of cases of acute monoblastic leukemia and 12% of cases of acute monocytic leukemia are associated with 11q23 genetic abnormalities involving the MLL gene. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) Mutation of FLT3, a receptor tyrosine kinase gene, has been observed in about 30% of cases of acute monocytic leukemia (approximately 7% in acute monoblastic leukemia). The translocation t(8;16)(p11; p13) (strongly associated with acute monocytic leukemia, hemophagocytosis by leukemic cells, and a poor response to chemotherapy) fuses the MOZ gene (8p11) with the CBP gene (16p13). Median actuarial DFS for acute monocytic leukemia has been reported to be approximately 21 months.
Acute erythroid leukemias (FAB classifications M6a and M6b)
The two subtypes of the acute erythroid leukemias, erythroleukemia and pure erythroid leukemia, are characterized by a predominant erythroid population and, in the case of erythroleukemia, the presence of a significant myeloid component. Erythroleukemia (erythroid/myeloid; M6a) is predominantly a disease of adults, comprising approximately 5% to 6% of cases of AML. Pure erythroid leukemia (M6b) is rare and occurs in all age groups. Occasional cases of chronic myeloid leukemia (CML) may evolve to one of the acute erythroid leukemias. Erythroleukemia may present de novo or evolve from an MDS, either RAEB or RCMD-RS or RCMD. (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) The clinical features of these acute leukemias include profound anemia and normoblastemia. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and cytochemical features of erythroleukemia include the following:
- 50% or more erythroid precursors in the entire nucleated cell population of the bone marrow.
- 20% or more myeloblasts in the nonerythroid population in the bone marrow.
- Dysplastic erythroid precursors with megaloblastoid nuclei.
- Multinucleated erythroid cells.
- Myeloblasts of medium size, occasionally with Auer rods.
- Ringed sideroblasts.
- Positive PAS stain in the erythroid precursors.
- Hypercellular bone marrow.
- Megakaryocytic dysplasia.
Morphologic and cytochemical features of pure erythroid leukemia include the following:
- Medium- to large-sized erythroblasts with round nuclei, fine chromatin, one or more nucleoli, deeply basophilic cytoplasm, and occasional coalescent vacuoles.
- Erythroblasts reactive with alpha-naphthyl acetate esterase.
- Acid phosphatase.
Immunophenotyping in erythroleukemia reveals erythroblasts that react with antibodies to glycophorin A and hemoglobin A and myeloblasts that express a variety of myeloid-associated antigens (CD13, CD33, CD117, c-kit, and MPO). Immunophenotyping in acute erythroid leukemia reveals expression of glycophorin A and hemoglobin A in differentiated forms. Markers such as carbonic anhydrase 1, Gero antibody against the Gerbich blood group, or CD36 are usually positive. The differential diagnosis for erythroleukemia includes RAEB and AML with maturation with increased erythroid precursors and AML with multilineage dysplasia (involving ≥50% of myeloid or megakaryocyte-lineage cells). If erythroid precursors are 50% or more and the nonerythroid component is 20% or more, the diagnosis is erythroleukemia, whereas, if the nonerythroid component is less than 20%, the diagnosis is RAEB. The differential diagnosis for pure erythroid leukemia includes megaloblastic anemia secondary to vitamin B12 or folate deficiency, acute megakaryocytic leukemia, and ALL or lymphoma.
No specific chromosome abnormalities are described for these AMLs. Complex karyotypes with multiple structural abnormalities are common. Chromosomes 5 and 7 appear to be affected frequently.[57,67,68] One study indicates that abnormalities of chromosomes 5 and/or 7 correlate with significantly shorter survival times.
Acute megakaryoblastic leukemia (FAB Classification M7)
Acute megakaryoblastic leukemia, in which 50% or more of blasts are of the megakaryocyte lineage, occurs in all age groups and comprises approximately 3% to 5% of cases of AML. Clinical features include cytopenias; dysplastic changes in neutrophils and platelets; rare organomegaly, except in children with t(1; 22); lytic bone lesions in children; and association with mediastinal germ cell tumors in young adult males.[57,70,71]
- Medium- to large-sized megakaryoblasts with round or indented nucleus and one or more nucleoli.
- Agranular, basophilic cytoplasm with pseudopod formation.
- Lymphoblast-like morphology (high nuclear-cytoplasmic ratio) in some cases.
- Circulating micromegakaryocytes, megakaryoblastic fragments, dysplastic large platelets, and hypogranular neutrophils.
- Stromal pattern of marrow infiltration mimicking a metastatic tumor in infants.
- Negative stains for SBB and MPO.
- Blasts reactive with PAS, acid phosphatase, and nonspecific esterase.
Immunophenotyping reveals megakaryoblast expression of one or more platelet glycoproteins: CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa). Myeloid markers CD13 and CD33 may be positive; CD36 is typically positive. Blasts are negative with the anti-MPO antibody and other markers of myeloid differentiation. In bone marrow biopsies, megakaryocytes and megakaryoblasts may react positively to antibodies for Factor VIII. The differential diagnosis includes minimally differentiated AML, acute panmyelosis with myelofibrosis, ALL, pure erythroid leukemia, and blastic transformation of chronic myeloid leukemia or idiopathic myelofibrosis and metastatic tumors in the bone marrow (particularly in children). (Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information on chronic myeloid leukemia or idiopathic myelofibrosis).
No unique chromosomal abnormalities are associated with acute megakaryoblastic leukemia in adults.[57,73] In children, particularly infants, a distinct clinical presentation may be associated with t(1:22)(p13; q13).[70,72] The prognosis for this type of acute leukemia is poor.[74,75]
Variant: Acute myeloid leukemia/transient myeloproliferative disorder in Down syndrome
Individuals with Down syndrome (trisomy 21) have an increased disposition to acute leukemia, primarily the myeloid type.[76,77] The primary subtype appears to be acute megakaryoblastic leukemia. In cases in which the leukemia remits spontaneously, the process is referred to as transient myeloproliferative disorder or transient leukemia. Clinical features include presentation in the neonatal period (10% of newborn infants with Down syndrome), marked leukocytosis, blast percentage in the blood greater than 30% to 50%, and extramedullary involvement.
Morphologic and cytochemical features include the following:
- Blasts with round to slightly irregular nuclei and a moderate amount of basophilic cytoplasm.
- Coarse azurophilic granules in the cytoplasm that resemble basophil granules.
- Promegakaryocytes and micromegakaryocytes.
- MPO-negative and SBB-negative blasts.
Immunophenotyping reveals markers that are generally similar to those of other cases of childhood acute megakaryoblastic leukemia.
In addition to trisomy 21, some cases may show other clonal abnormalities, particularly trisomy 8.[77,78] Spontaneous remission occurs within 1 to 3 months in transient cases. Recurrence followed by a second spontaneous remission or persistent disease may occur. Treatment outcomes for pediatric patients with Down syndrome and persistent disease may be better than those for pediatric patients with acute leukemia in the absence of trisomy 21.
Acute basophilic leukemia
Acute basophilic leukemia is an AML that exhibits a primary differentiation to basophils. This acute leukemia is relatively rare, comprising less than 1% of all cases of AML. Clinical features include bone marrow failure, circulating blasts, cutaneous involvement, organomegaly, occasional osseous lytic lesions, and symptoms secondary to hyperhistaminemia.
Morphologic and cytochemical features include the following:
- Medium-sized blasts with a high nuclear-cytoplasmic ratio and an oval, round, or bilobed nucleus with one or more nucleoli.
- Moderately basophilic cytoplasm containing a variable number of coarse basophilic granules.
- Sparse numbers of mature basophils.
- Dysplastic erythroid features.
- Blasts with metachromatic positivity, with toluidine blue.
- Blasts with acid phosphatase positivity.
- Negative by light microscopy for SBB, MPO, and nonspecific esterase.
- Hypercellular bone marrow.
Immunophenotypically, the blasts express the myeloid markers CD13 and CD33 and the early hematopoietic markers CD34 and class-II HLA-DR. The differential diagnosis includes: blast crisis of CML, other AML subtypes with basophilia such as AML with maturation (M2) associated with abnormalities of 12p or t(6;9), acute eosinophilic leukemia, and, rarely, a subtype of ALL with prominent coarse granules.
No consistent chromosome abnormality has been identified for acute basophilic leukemia. Because of its rare incidence, little information regarding survival is available.
Acute panmyelosis with myelofibrosis
Acute panmyelosis with myelofibrosis (also known as acute myelofibrosis, acute myelosclerosis, and acute myelodysplasia with myelofibrosis) is an acute panmyeloid proliferation associated with fibrosis of the bone marrow. This disorder is very rare and occurs in all age groups. The disorder may occur de novo or after treatment with alkylating-agent chemotherapy and/or radiation (Refer to the Acute myeloid leukemias and myelodysplastic syndromes, therapy related section of this summary for more information). Clinical features include constitutional symptoms such as weakness and fatigue. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and cytochemical features include the following:
- Marked pancytopenia.
- Dysplastic changes in myeloid cells.
- Hypercellular bone marrow (biopsy).
- Variable degrees of hyperplasia of erythroid precursors, granulocytes, and megakaryocytes in the bone marrow.
- Increased number of small- to large-sized megakaryocytes with dysplastic features in the bone marrow.
- Marked increase in reticulin fibers in the bone marrow.
Immunophenotypically, blasts may express one or more myeloid-associated antigens (CD13, CD33, CD117, and MPO). Some cells may express erythroid or megakaryocytic antigens. The major differential diagnosis includes acute megakaryoblastic leukemia, acute leukemias with associated marrow fibrosis, metastatic tumor with a desmoplastic reaction, and chronic idiopathic myelofibrosis. (Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information.)
No specific chromosomal abnormalities are associated with acute panmyelosis with myelofibrosis. This AML is reported to respond poorly to chemotherapy and to be associated with a short survival.
Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site; development in 2% to 8% of patients with AML has been reported. Clinical features include occurrence common in subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis; lymph nodes, skin, mediastinum, small intestine, and the epidural space; and occurrence de novo or concomitant with AML or a myeloproliferative disorder.[57,79]
Morphologic and cytochemical features include the following:
- Granulocytic sarcoma composed of myeloblasts, neutrophils, and neutrophil precursors with three subtypes based on degree of maturation (i.e., blastic, immature, and differentiated).
- Monoblastic sarcoma preceding or occurring simultaneously with acute monoblastic leukemia.
- Tumors with trilineage hematopoiesis occurring with transformation of chronic myeloproliferative disorders.
- Myeloblasts and neutrophils that are positive for MPO.
- Neutrophils that are positive for naphthol ASD chloroacetate esterase.
Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate are critical to the diagnosis of these lesions. The myeloblasts in granulocytic sarcomas express myeloid-associated antigens (CD13, CD33, CD117, and MPO). The monoblasts in monoblastic sarcomas express acute monoblastic leukemia antigens (CD14, CD116, and CD11c) and usually react with antibodies to lysozyme and CD68. The main differential diagnosis includes non-Hodgkin lymphoma of the lymphoblastic type, Burkitt lymphoma, large-cell lymphoma, and small, round-cell tumors, especially in children (e.g., neuroblastoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumors, and medulloblastoma).
No unique chromosomal abnormalities are associated with myeloid sarcoma.[57,79] AML with maturation and t(8; 21)(q22; q22) and AMML Eo with-in (16)(p13; q22) or t(16;16)(p13; q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23. The presence of myeloid sarcoma in patients with the otherwise good-risk t(8; 21) AML may be associated with a lower CR rate and decreased remission duration. Myeloid sarcoma occurring in the setting of MDS or MPD is equivalent to blast transformation. In the case of AML, the prognosis is that of the underlying leukemia. Although the initial presentation of myeloid sarcoma may appear to be isolated, several reports indicate that isolated myeloid sarcoma is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.[79,81,82]
Acute Leukemias of Ambiguous Lineage
Acute leukemias of ambiguous lineage (also known as acute leukemias of undetermined lineage, mixed phenotype acute leukemias, mixed lineage acute leukemias, and hybrid acute leukemias) are types of acute leukemia in which the morphologic, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphologic and/or immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (i.e., acute bilineal leukemia and acute biphenotypic leukemia).[83-87] These rare leukemias account for less than 4% of all cases of acute leukemia and occur in all age groups but are more frequent in adults. Clinical features include symptoms and complications caused by cytopenias, i.e., fatigue, infections, and bleeding disorders. (Refer to the PDQ summary on Fatigue for more information.)
- Undifferentiated acute leukemia in which the leukemic cells lack any differentiating characteristics and lack markers for a given lineage.
- Bilineal acute leukemia in which a dual population of blasts exhibits morphologic features and markers of two distinct lineages, i.e., myeloid and lymphoid or B and T.
- Biphenotypic acute leukemia in which the blasts exhibit the morphological features of only one lineage but express markers of more than one lineage.
The differential diagnosis includes myeloid antigen-positive ALL or lymphoid-positive AML (from which biphenotypic acute leukemia should be distinguished) and minimally differentiated AML (from which undifferentiated acute leukemia must be distinguished).
Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias.[84,85,88,89] Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4; 11)(q21; q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable, particularly in adults; the occurrence of the translocation t(4; 11) or the Philadelphia chromosome are especially unfavorable prognostic indicators.[83,85,90]
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