Introduction

Leukemia is the most common childhood cancer. Unlike leukemia in adults, childhood leukemia is acute in the vast majority of cases. The most common subtype, acute lymphoblastic (also termed lymphocytic or lymphoid) leukemia (ALL), accounts for 75% to 80% of all cases of childhood leukemia, whereas acute myeloid (also termed myelocytic, myelogenous, or nonlymphoblastic) leukemia (AML) comprises approximately 20%.

Acute leukemia is a malignant proliferation and accumulation of immature lymphohematopoietic cells. The leukemic cell population is shown to be clonal by cytogenetics, glucose-6-phosphate dehydrogenase characterization, and analysis of antigen-receptor gene rearrangements and X-linked restriction fragment-length polymorphisms.¹ Although leukemic cells generally do not proliferate as actively as their normal hematopoietic counterparts,² they accumulate inexorably and compete successfully with normal cells. Their inability to differentiate and their relative resistance to apoptosis may explain this phenomenon. By the time of diagnosis, leukemic cells have usually replaced normal bone marrow cells and disseminated to various extramedullary sites. Therefore the presenting features of leukemia typically reflect the degree of bone marrow replacement and the extent of extramedullary spread.

Both ALL and AML are heterogeneous diseases that comprise different biological subtypes. The major morphologic and immunophenotypic divisions based on lineage association and degree of maturation are subclassified by the identification of distinct, recurrent chromosomal and molecular abnormalities,3,4 and gene expression patterns.^5–9

Chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and myeloproliferative disorders (MPD) are infrequent in children. In general, they share clinical, laboratory, and morphologic features with one of their adult counterparts.10–13 A disorder characterized by an heterogeneous pattern of myeloproliferation, dysplasia, and hepatosplenomegaly in association with abnormal peripheral blood counts has historically been called “juvenile CML,” “infantile monosomy 7 syndrome,” and “chronic myelomonocytic leukemia” by different authors; the term juvenile myelomonocytic leukemia (JMML) is currently favored.¹⁴ Only a few well-documented cases of chronic lymphocytic leukemia have been reported in children.^15,16

Epidemiology

Leukemia is the most common malignancy among patients younger than 15 years. ALL is approximately four times more common than AML. Males are generally affected by leukemia slightly more often than females in all age groups, with two exceptions: boys have a risk of T-cell leukemia that is four times that of girls, and girls have a slightly higher incidence of leukemia in the first year of life (1.5 : 1 ratio).¹⁷ Rates of ALL are comparatively higher in Northern and Western Europe, North America, and Oceania, than in Asia and Africa.¹⁷ In developed countries, the incidence of ALL is highest between ages 2 and 5 years. This age peak is accounted for largely by ALL with hyperdiploidy (>50 chromosomes) or ETV6-RUNX1 (formerly known as TEL-AML1) gene fusion.³ The incidence of ALL is higher in the Hispanic than in the white population, which, in turn, is higher than in the black population, especially among children 2 to 5 years of age. Black children have a higher incidence of T-cell ALL and pre-B leukemia with E2A-PBX1 fusion, and are less likely to have hyperdiploid ALL with more than 50 chromosomes than are white children.¹⁸ The incidence of AML in children peaks at 2 years of age, decreases to a nadir at 9 years, then peaks again at around age 16 years.¹⁹ The highest incidence of pediatric AML occurs among the Maori of New Zealand, Hawaiian Americans, and Africans in Zimbabwe.¹⁹ In most populations of children, less than 10% of cases of AML are acute promyelocytic leukemia.²⁰ However, this figure is approximately 25% in children of Latin American origin²¹; a higher incidence was also reported in Italian children.²² Pediatric patients with MDS are typically older at diagnosis (>5 years old), whereas JMML nearly always occurs before 5 years of age.¹⁴

A small percentage (<5%) of cases of leukemia are associated with inherited genetic syndromes (Table 96-1). Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia (ALL and AML).^23,24 Furthermore, a MPD termed transient abnormal myelopoiesis may occur in newborns with Down syndrome.²⁵ This disorder spontaneously remits in almost all patients within 3 months. However, early death can occur in almost 20% of patients with high presenting leukocyte count, abnormal liver function, and failure to normalize blood count; AML subsequently develops in another 30% of patients.²⁵ Several other genetic disorders are associated with an increased risk of leukemia and/or MDS, including ataxia-telangiectasia, Wiskott-Aldrich syndrome, Bloom syndrome, Fanconi anemia, Kostmann disease, Blackfan-Diamond anemia, and neurofibromatosis.^19,26,27 The association between leukemia and congenital immunodeficiencies, such as X-linked agammaglobulinemia and common variable immunodeficiency, is not well supported.²⁶

Fraternal twins and siblings of affected children are at a twofold to fourfold greater risk of leukemia during the first decade of life than unrelated children.17,28 However, a Nordic population- and register-based study failed to show an increased incidence among siblings of children with leukemia.²⁹ When leukemia occurs in one identical twin, the likelihood that the other twin will develop the disease is approximately 20%. However, when leukemia is diagnosed in one twin before 1 year of age, it almost invariably develops in the other twin, typically within a few months. Molecular studies have demonstrated that intrauterine metastasis of ALL from one twin to the other, via the shared placental circulation, is responsible for the concordant leukemia.^32–32

Etiology

Although environmental agents, such as ionizing radiation and chemical mutagens, have been implicated in the induction of leukemia, discernible etiologic factors are lacking in almost all cases of primary leukemia.¹⁷ Association between leukemia and maternal exposure to various potential mutagens, neonatal administration of vitamin K, parental use of medications and drugs, and proximity to electromagnetic fields has not been authoritatively demonstrated.¹⁷ Although an association between increased risk of childhood ALL and exposure to high levels of residential magnetic fields has been reported, this finding needs confirmation.^35–35 A case-control study identified a significantly increased risk of leukemia among the offspring of men employed in occupations with a risk of exposure to electromagnetic fields or radiation,³⁶ a finding that also warrants further studies. Because industrialization, higher socioeconomic status and social isolation are associated with an increased risk of B-lineage ALL, Greaves hypothesized that abnormally late exposure to common infections and immune response stimulation could enhance the likelihood of leukemogenic genetic mutations, thus increasing the risk of childhood B-lineage ALL.³⁷ In line with this notion is the observation of occasional clustering of childhood ALL associated with rural-urban population mixing, especially in new towns.^38,39

Infant leukemias frequently have rearrangements of the MLL gene, located on chromosome band 11q23.40,41 MLL rearrangements are also common in therapy-related AML, arising after treatment with topoisomerase II inhibitors.⁴² This molecular similarity raised the hypothesis that transplacental fetal exposure to substances that inhibit topoisomerase II, such as flavonoids (in food and drink), quinolone antibiotics, benzene metabolites, catechins, and estrogens, could be leukemogenic.⁴¹ A case-control study found that in utero exposure to DNA-damaging drugs, herbal medicines, or pesticides was significantly associated with infant leukemia with MLL rearrangements.⁴³ Because the functional doses received via dietary and environmental exposure are much lower than those received from anticancer chemotherapy, it was postulated that affected infants or their mothers may have reduced activity of carcinogen-detoxifying enzymes because of genetic polymorphism. In this regard, deficiency of glutathione-S-transferases (GST-M1 and GST-T1), enzymes that detoxify electrophilic metabolites by catalyzing their conjugation to glutathione, is associated with infant leukemia without MLL rearrangement,⁴¹ and with ALL in black children.⁴⁴ Polymorphisms of reduced nicotinamide adenine dinucleotide phosphate : quinone oxidoreductase, an enzyme that converts benzoquinones to less toxic hydroxyl metabolites, have been associated with the development of infant and childhood ALL.^45,46 Cytochrome P-450 CYP1A1*2A and NQO1*2 variant genotypes have also been linked to an increased risk of childhood ALL; children carrying both genotypes were at a particularly high risk.⁴⁷ It has also been suggested that folate pathways may play a role in susceptibility to ALL,^48,49 and that folate supplement may reduce the risk,⁵⁰ an intriguing finding that requires confirmation. However, recent genome-wide associated studies could not confirm those findings and instead identified a number of other inherited polymorphisms in genes such as ARID5B, IKZF1, CEBPE, and CDKN2A, that are associated with the risk of childhood ALL in various ethnic and racial groups.^51–54 To date, no direct gene-environment interaction has been firmly established.

Pathogenesis

There is strong evidence that acquired genetic changes are central to the development of leukemia. These changes affect the number (ploidy) and/or the structure of chromosomes; structural changes comprise translocations, inversions, deletions, point mutations, and amplifications.⁵⁵ The dysregulation of genes encoding transcription factors and the resulting subversion of transcriptional pathways that regulate hematopoietic cell homeostasis, provides a mechanistic explanation for leukemogenesis.^56,57 For example, the core binding factor (CBF) family of transcription factors is disrupted by recurrent chromosomal translocations, such as those involving ETV6-RUNX1 in ALL and RUNX1-RUNX1T1 and CBFB–MYH11 in AML.^57,58 The encoded proteins regulate the expression of growth factors, such as interleukin-3, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor receptor, as well as the T-cell receptor β enhancer and the immunoglobulin heavy chain enhancer/promoter. The function of homeobox (HOX) genes, an evolutionarily highly conserved family of transcription factors whose expression is tightly regulated during hematopoietic cell differentiation, can also be disrupted either by direct involvement in chromosomal translocations [e.g., the t(7;11), forming the NUP98-HOXA9 fusion gene] or by the disruption of proteins believed to be their upstream regulators.⁵⁹ Among the latter, the most notable is encoded by MLL, a gene crucial for both embryonic development and hematopoiesis, and, as mentioned above, is involved in translocations of the 11q23 region in both ALL and AML.^58,59 Chimeric proteins encoded by fused genes can also directly interfere with normal apoptotic pathways, as has been demonstrated in the case of the TCF3-HLF protein.^60,61 The expression of key regulators can be altered in the absence of detectable genetic abnormalities. For example, five different T-cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) can be aberrantly expressed in T-lineage ALL in the absence of chromosomal abnormalities.⁶

Cell survival requirements can be altered by the dysregulated activity of tyrosine kinases, as in the case of the BCR-ABL1 gene fusion.⁴ Alternatively, activating mutations in tyrosine kinase receptors for growth factors may confer a growth advantage to leukemic cells. This mechanism is exemplified by mutations of FLT3, which encodes a receptor tyrosine kinase expressed by immature hematopoietic cells that acts synergistically with other growth factors to stimulate proliferation of hematopoietic progenitor cells.⁶² Mutant FLT3 is detectable in both ALL and AML; these mutations typically involve small tandem duplications of amino acids that result in constitutive tyrosine kinase activity.⁶² Activating mutations of NOTCH1, a gene encoding a transmembrane receptor that regulates normal T-cell development, are frequently detected in T-cell ALL.^63,64 Activating mutations of NOTCH1 produce constitutive NOTCH1 signaling, which is sufficient to induce T-cell ALL in experimental models.⁶⁴ Gamma secretase, a multicomponent membrane-associated enzyme, is required for NOTCH1 signaling through mutant NOTCH receptors in T-cell ALL, providing a target for therapeutic intervention with γ-secretase inhibitors.⁶⁵ NOTCH signaling can also be interfered with by directly targeting NOTCH receptors with specific antibodies,⁶⁶ thus avoiding the toxicity associated with γ-secretase inhibitors. Interestingly, somatic mutations inactivating the NOTCH pathway have been identified in some patients with chronic myelomonocytic leukemia, suggesting that NOTCH can also have tumor-suppressive functions.⁶⁷

A pioneering large-scale study of DNA single-nucleotide polymorphism (SNP) analysis examined 242 cases of pediatric ALL and identified lesions in genes encoding key regulators of B-cell differentiation in 40% of B-cell precursor ALL cases.⁶⁸ Most prominent were deletions and cryptic translocations involving the PAX5 gene, which was altered in almost one third of cases, and which would be predicted to block normal B-progenitor cell differentiation before immunoglobulin heavy-chain gene rearrangement. Other mutated genes were found in concert with several of the more common translocation-induced chimeric oncogenes, such as TCF3-PBX1 and ETV6-RUNX1, including the essential B-cell developmental genes E2A, EBF, LEF1, Ikaros, and Aiolos.

The retrospective identification of leukemia-specific fusion genes (e.g., MLL-AFF1, ETV6-RUNX1) in the neonatal blood spots of identical twins who experienced concordant leukemia has demonstrated their prenatal origin.32,69 In cases with the t(4;11) and MLL-AFF1, there is a high rate of concordance in identical twins (25% to 100%) and a very brief latency period after birth (a few weeks to a few months).³² In other types of leukemia, for example, those with the ETV6-RUNX1 fusion or T-cell phenotype, the rate of concordance is lower, the postnatal latency period is longer and is variable, and the clinical presentation and the outcome of therapy may differ widely among identical twins, suggesting that secondary postnatal molecular events are necessary for full leukemic transformation.³² Further insights were gained from a report of a set of triplets in which the two monozygotic twins developed concordant leukemia with identical ETV6-RUNX1 fusion at 3 years of age, while the third child, who had developed from a second zygote, was free of leukemia and of the genomic sequence.³¹ In addition to the fusion transcript, the identical twins had a secondary, independent deletion of the normal unrearranged ETV6 allele, suggesting a contributing postnatal event. Clone-specific antigen receptor gene rearrangements were analyzed in the neonatal blood spots of five children who were 6 months to 4 years and 8 months of age at diagnosis of B-lineage ALL and T-ALL: in all five children, the clonotypic antigen receptor gene rearrangements had been present at birth and the estimated number of clonotypic cells per blood spot was in the range of 10 to 100.⁷⁰ One study found the ETV6-RUNX1 fusion in the cord blood of approximately 1% of randomly selected newborns, a frequency approximately 100 times that of ALL with ETV6-RUNX1,⁷¹ further supporting the notion that preleukemic clones are generated in utero at a high frequency and that secondary postnatal leukemogenic events are required for a fully malignant transformation of ETV6-RUNX1 cells. The prevalence of leukemias with prenatal origin is not known and not all cases develop in utero. For example, t(1;19) E2A-PBX1 ALL appears to have a postnatal origin in most cases.⁷² There is also evidence for RUNX1-RUNXT1 gene fusions occurring in utero,⁷³ but the precise frequency of in utero events for this and other type of genetic abnormalities associated with AML is unclear.⁷⁴

General Clinical and Laboratory Features

Physical examination of children with leukemia may reveal pallor, petechiae, ecchymoses, and mucosal bleeding. If thrombocytopenia and hyperleukocytosis are severe, there may be life-threatening bleeding (e.g., intracranial hematoma). Anemia may cause fatigue and lethargy, dyspnea, angina, and dizziness. Neutropenia may lead to severe infection. Bone pain and arthralgia caused by leukemic infiltration or, less frequently, hemorrhage is more common in ALL than AML and may be especially severe in young children. Patients may be seen with fever, which may be induced by infection or by pyrogenic cytokines (e.g., interleukin-1, interleukin-6, and tumor necrosis factor) released from the leukemic cells. Liver, spleen, thymus, and lymph nodes are common sites of extramedullary involvement; however, in AML, massive hepatosplenomegaly is common only in infants. Infiltration of the central nervous system (CNS) is seen in children with ALL or AML. An anterior mediastinal (thymic) mass is typical of T-cell ALL. Painless enlargement of the scrotum can be a sign of testicular leukemia or hydrocele resulting from lymphatic obstruction. Testicular involvement is rare in AML. In patients with AML, common sites of extramedullary disease include the skin, gums, and the neck and head area. Myeloblastomas (granulocytic sarcomas, chloromas) are solid tumors composed of myeloblasts that may precede overt bone marrow involvement of AML. They typically occur in the skin, soft tissue, bones, and CNS, but may develop in virtually any tissue or organ. Very rarely, acute leukemia produces no signs or symptoms and is detected during routine examination.

Anemia, neutropenia, and thrombocytopenia are common findings, and their severity reflects the degree of bone marrow replacement by leukemic cells. The presenting leukocyte count ranges from 0.1 to 1500 × 10⁹/L (median: 10 to 12 × 10⁹/L); hyperleukocytosis (>100 × 10⁹/L) occurs in 15% to 18% of cases of ALL and AML. Most patients have circulating leukemic blast cells. A large leukemic cell burden is commonly accompanied by elevated serum lactate dehydrogenase activity and elevated uric acid and phosphorus concentration. Some patients with T-cell ALL are seen with normal red blood cell and platelet counts. In these cases, the lymphoblasts in the bone marrow usually represent the leukemic phase of an extramedullary lymphoblastic lymphoma. Not infrequently, the marrow contains a significant population of nonleukemic myeloblasts, which may be difficult to distinguish morphologically from the leukemic cells.

Leukemic blast cells are identified at diagnosis in the cerebrospinal fluid (CSF) of as many as one third of children with ALL (most of whom have no neurologic symptoms) and in approximately 5% of children with AML. Traditionally, CNS leukemia is defined by the presence of at least 5 leukocytes per microliter of CSF and the detection of leukemic blast cells, or by the presence of cranial nerve palsy. However, the presence of any amount of leukemic cells in CSF, even from iatrogenic introduction as the result of a traumatic lumbar puncture, is associated with an increased risk of ALL relapse, and requires additional intrathecal therapy.75,76

Pancytopenia is a presenting feature in most cases of MDS.¹³ Fetal hemoglobin is frequently slightly elevated. Most patients have no organomegaly. Extramedullary myeloid tumor may be the presenting feature of MDS but blasts in the CSF is not seen in MDS. The bone marrow is usually normocellular or hypercellular, with characteristic dysplastic features, including megaloblastic erythropoiesis, bizarre small or unusual large megakaryocytes, and dysgranulopoiesis; the percentage of myeloblasts is often increased.¹³ Hepatosplenomegaly and lymphadenopathy are suggestive clinical features of JMML.¹⁴ Current World Health Organization diagnostic criteria for patients with JMML include a peripheral monocyte count greater than 1 × 10⁹/L with less than 20% bone marrow blasts and splenomegaly in the absence of BCR-ABL1. Other characteristic features of JMML are somatic mutation in RAS or PTPN11, clinical diagnosis of NF1 or NF1 gene mutation, and/or monosomy 7. A feature of JMML cells is their capacity to spontaneously form granulocyte-macrophage colonies in vitro, and their hypersensitivity to granulocyte-macrophage colony-stimulating factor.¹⁴

Differential Diagnosis

The acute onset of petechiae, ecchymoses, and bleeding may suggest idiopathic thrombocytopenic purpura (often associated with a recent viral infection, large platelets in blood smears, and no evidence of anemia). Both acute leukemia and aplastic anemia may present with pancytopenia and complications associated with bone marrow failure, but in aplastic anemia, hepatosplenomegaly and lymphadenopathy are rare, and the skeletal changes associated with leukemia are absent.

Infectious mononucleosis and other viral infections can be confused with ALL. Detection of atypical lymphocytes or elevated viral titers aid in the diagnosis. Patients with pertussis or parapertussis may have marked lymphocytosis, but the affected cells are mature lymphocytes rather than lymphoblasts. Bone pain, arthralgia, and occasionally arthritis may mimic juvenile rheumatoid arthritis, rheumatic fever, other collagen diseases, or osteomyelitis.

Childhood ALL should also be distinguished from pediatric small round cell tumors that involve the bone marrow, including neuroblastoma, rhabdomyosarcoma, and retinoblastoma. Generally, in such cases, a primary lesion can be found by routine diagnostic studies, and disseminated tumor cells often form clumps.

MDS with a low blast count must be distinguished from aplastic anemia and other nonclonal disorders, which often requires sequential morphologic studies, including bone marrow biopsies.¹³ Myelodysplasia may also occur in a variety of disorders, such as infection, drug therapy, and chronic disease. AML is the major differential diagnosis of MDS. Cases with AML-specific translocations are more appropriately classified as AML regardless of the blast count, whereas monosomy 7 as the only cytogenetic aberration is strongly suggestive of MDS.¹³ A definitive distinction between JMML and Philadelphia chromosome-positive CML requires karyotypic or molecular examination for the t(9;22)/BCR-ABL1 abnormality. These conditions also must be distinguished from the “leukemoid reaction” associated with infection, cancer, or congenital heart disease in which signs and symptoms do not progress and/or resolve spontaneously.¹⁴

Morphologic and Cytochemical Analysis

Morphologic analysis of leukemic cells in smears stained with Romanowsky stains (Wright-Giemsa or May-Grünwald-Giemsa) distinguishes three subtypes of ALL (L1, L2, and L3) and eight subtypes of AML (M0-M7) as classified by the French–American–British (FAB) scheme (Fig. 96-1).⁷⁷ However, the FAB classification for ALL is no longer used because the defining criteria are too subjective, and it has no prognostic or therapeutic significance. The term acute myeloid leukemia is used to designate even leukemias in which some or all cells have the morphology of monocytes (M4, M5), erythroblasts (M6), or megakaryoblasts (M7). Because of the rarity and heterogeneous nature of childhood MDS, its classification has been inconsistent.¹³ Analysis of a Romanowsky-stained smear cannot accurately distinguish between ALL and AML. Cytochemical stains help this distinction. Myeloperoxidase, Sudan black, and nonspecific esterases, including α- naphthyl butyrate and α-naphthyl acetate esterase, react with myeloid blast cells, whereas periodic acid-Schiff reagent reacts positively in more than 70% of ALL cases. However, despite the traditional use of morphology and cytochemistry, contemporary classification of acute leukemias is based on subtypes that can be identified only by immunologic and molecular analyses.

The FAB group classified MDS into five subgroups: refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia.⁷⁸ AML was defined by the presence of 30% myeloblasts in the bone marrow. A more recent World Health Organization classification classified myelodysplastic and myeloproliferative disorders into MDS, JMML, and myeloid leukemias of Down syndrome (Table 96-2).^10,13 The distinction between MDS and AML can be difficult and may require molecular genetic studies. The presence of greater than 30% of blasts in the blood or marrow suggests AML, whereas less than 20% blasts suggests MDS.¹³

Table 96-3 summarizes antigen expression patterns in ALL.

Rare Acute Leukemias

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