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Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For acute myeloid leukemia (AML), the 5-year survival rate increased over the same time from less than 20% to 68% for children younger than 15 years and from less than 20% to 57% for adolescents aged 15 to 19 years.
Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children
Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies. The majority of myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia and juvenile myelomonocytic leukemia. Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that may evolve from congenital marrow failure syndromes such as Fanconi anemia and Shwachman-Diamond syndrome.
The general characteristics of myeloid leukemias and other myeloid malignancies are described below:
TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene.[6,7] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML. Approximately 20% of infants with TAM of Down syndrome eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8]
Early death from TAM-related complications occurs in 10% to 20% of affected infants.[8,9,10] Infants with progressive organomegaly, visceral effusions, high blast count (>100,000 cells/µL) and laboratory evidence of progressive liver dysfunction are at a particularly high risk of early mortality.[8,10] (Refer to the Children With Down Syndrome and AML or Transient Abnormal Myelopoiesis [TAM] section of this summary for more information.)
The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. (Refer to the Myelodysplastic Syndromes [MDS] section of this summary for more information.)
JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes. In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[12,13,14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)
CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes. (Refer to the Chronic Myelogenous Leukemia [CML] section of this summary for more information.)
Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.
Conditions Associated With Myeloid Malignancies
Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[15,16,17] There is an estimated twofold to fourfold increased risk of developing leukemia for the fraternal twin of a pediatric leukemia patient up to about age 6 years, after which the risk is not significantly greater than that of the general population.[18,19]
The development of AML has also been associated with a variety of inherited, acquired, and familial syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[20,21]
Familial MDS and AML syndromes
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.
French-American-British (FAB) Classification System for Childhood AML
The first comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1,2,3,4,5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.
The major subtypes of AML include the following:
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).
World Health Organization (WHO) Classification System for Childhood AML
In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[8,9,10]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system. In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia. With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will certainly continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.
2016 WHO classification of AML and related neoplasms
2016 WHO classification of acute leukemias of ambiguous lineage
For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[13,14] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.
Leukemias of mixed phenotype may be seen in various presentations, including the following:
Biphenotypic cases represent the majority of mixed phenotype leukemias. B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission (CR) and a significantly worse event-free survival (EFS) compared with patients with precursor B-cell ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[16,17,18] although the optimal treatment for patients remains unclear.
WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes
The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[19,20] Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:[20,21,22,23]
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD. The 2016 revision to the WHO classification has removed focus on the specific lineage (anemia, thrombocytopenia, or neutropenia) and now distinguishes cases with dysplasia in single versus multiple lineages. For patients with MDS and excess blasts (5%–20%), the terminology has changed (refractory anemia with excess blasts [RAEB]-1 and RAEB-2 designations are now MDS with excess blasts [MDS-EB]-1 and MDS-EB-2). No changes were made in the childhood MDS classification, and the category of refractory cytopenia of childhood is retained as a provisional entity. The bone marrow and peripheral blood findings for the myelodysplastic syndromes according to the 2008 WHO classification schema are summarized in Tables 3 and 4.[12,24]
Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS, however, the WHO 2016 guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.
A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003. A retrospective comparison of the WHO classification to the Category, Cytology, and Cytogenetics system (CCC) and to a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems appear to more effectively classify childhood MDS than the more general WHO system. For instance, refractory anemia with ring sideroblasts is rare in children, and refractory anemia and refractory anemia with excess blasts is more common. When such refractory cytopenias with excess blasts (5%–20%) are associated with recurrent cytogenetic abnormalities usually associated with AML, a diagnosis of the latter should be made and treated accordingly.
The WHO classification schema under myelodysplastic/myeloproliferative neoplasms has a subgroup that includes juvenile myelomonocytic leukemia (JMML) (formerly juvenile chronic myeloid leukemia), chronic myelomonocytic leukemia (CMML), and Philadelphia chromosome (Ph)–negative chronic myelogenous leukemia (CML). This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML [26,27,28] but is a distinct syndrome (refer to Table 8 below). A subgroup of children younger than 4 years at diagnosis with JMML associated with monosomy 7 are considered to have a subtype of JMML characterized by lower WBC count, higher percentage of circulating monocytes, higher mean cell volume for red blood cells, a lower bone marrow myeloid to erythroid ratio, and, often, normal to moderately increased fetal hemoglobin.
The International Prognostic Scoring System is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or JMML, only a blast count of less than 5% and a platelet count of more than 100 x 109 /L were associated with a better survival in MDS, and a platelet count of more than 40 x 109 /L predicted a better outcome in JMML. These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.
MDS in children with monosomy 7 and high-grade MDS behaves more like MDS in adults and are best classified as adult MDS and treated with allogeneic hematopoietic stem cell transplantation.[30,31] The risk group or grade of MDS is defined according to International Prognostic Scoring System guidelines.
Diagnostic and Molecular Evaluation
The treatment for children with AML differs significantly from that for ALL. As a consequence, it is critical to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, periodic acid-Schiff, Sudan Black B, and esterase. In most cases, the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (refer to Table 5). Histochemical stains have been mostly replaced by flow cytometric immunophenotyping.
The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and acute leukemias of ambiguous lineage. The expression of various cluster determinant (CD) proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AML cases, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AML cases.[34,35,36] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[34,35]
Immunophenotyping can also be helpful in distinguishing the following FAB subtypes of AML: