Pediatric Leukemia and Lymphoma

Epidemiology

ALL accounts for approximately 75% of childhood leukemia and is diagnosed in approximately 2500 to 3000 children in the United States annually with a peak age incidence between 2 and 5 years. The incidence of ALL is higher among boys than girls. This difference is more pronounced in pubertal children and particularly evident in cases of T-cell ALL. In the United States, ALL occurs more commonly among white children than among African American children.

Etiology

Although there is no single etiology of ALL, several predisposing risk factors have been identified. These include genetics, environmental factors, viral infection, and immunodeficiency. Genetics appear to play a role in the cause of ALL in some children as evidenced by the association between specific chromosomal abnormalities and childhood ALL. The most common constitutional chromosomal abnormality associated with childhood leukemia is trisomy 21 or Down syndrome. However, the majority of cases of leukemia in children cannot be attributed to any known factors.

ALL comprises a very heterogenous group of diseases that can be defined by their cell of origin, state of maturation arrest, and oncogenic driver pathways and mutations. Although ALL is subclassified into B- and T-progenitor disease based on gene expression and presumed cell of origin, these diseases do share a common origin from the committed lymphoid progenitor. Therefore the clinically different behaviors of these two biologically distinct diseases are more likely the result of different underlying oncogenic driver events. In contrast, in both Philadelphia chromosome-positive ALL and in pediatric acute myeloid leukemia (AML) this event may occur earlier, as mutations are observed in multiple cell lineages. The sequence of events resulting in malignant transformation is likely to be multifactorial in all types of leukemia.

Molecular Biology and Classification

ALL has been classified according to morphological, immunological, cytogenetic, biochemical, and molecular genetic characteristics. The most widely accepted morphological classification of ALL is that proposed by the French-American-British (FAB) Cooperative Working Group. The FAB system defines three categories of lymphoblasts. The L1 subtype is the most common, occurring in approximately 90% of pediatric ALL. The L1 lymphoblasts are smaller, with scant cytoplasm and inconspicuous nucleoli. L2 lymphoblasts are seen in 5% to 15% of pediatric ALL and are larger, demonstrate marked heterogeneity in size, contain prominent nucleoli, and more abundant cytoplasm. Morphologically they can be difficult to distinguish from the M1 subtype of AML. L3 lymphoblasts, present in only 1% to 2% of cases, are large with more abundant, basophilic cytoplasm and often have cytoplasmic vacuolation. The L3 lymphoblast is morphologically identical to the Burkitt lymphoma cell. L3 morphology is almost always associated with a mature B-cell phenotype and translocations involving the MYC gene, and patients should be treated with therapy for Burkitt lymphoma rather than ALL.

Immunophenotyping

The immunobiological studies of ALL indicate that leukemic transformation and clonal expansion occurs at different stages of lymphocyte maturation. The use of monoclonal antibodies has classified leukemias; however, these monoclonal antibodies are not purely lineage-specific and so the term “lineage-associated” is used. Based on their patterns of reactivity to these lineage-associated antibodies, ALL can be subclassified into three primary types: B-precursor, mature B-cell, and T-cell. B-precursor cell ALL comprises 80% to 85% of pediatric ALL cases. These cells characteristically express B-cell markers such as CD 9, CD 19, CD 22, and in contrast to mature B-cell ALL they lack expression of surface immunoglobulin. Most cases of B-lineage ALL in children and adolescents are found to have the common ALL antigen CD 10 on their cell surfaces. Patients with B-precursor ALL whose lymphoblasts express the common ALL antigen or CD 10 on their surfaces have a more favorable prognosis than those who do not, primarily because of the strong association of CD 10 negativity with rearrangements of the MLL gene on chromosome 11q23.

Children with mature B-cell ALL (characterized by the presence of mature B-cell antigens, including surface immunoglobulin) have a poorer prognosis than those of earlier B-lineage if treated with standard ALL therapies; such patients are more appropriately treated on regimens for patients with advanced-stage Burkitt lymphoma. Approximately 10% to 15% of pediatric ALL is of T-cell origin. In contrast to B-precursor ALL, T-cell ALL is more frequently associated with older age at diagnosis, a higher presenting leukocyte count, and bulky extramedullary disease. Extramedullary involvement can include an anterior mediastinal mass, lymphadenopathy, hepatosplenomegaly, and overt CNS involvement. T-cell ALL has on average a shorter time to relapse than does B-precursor ALL. Although historically T-cell ALL had a worse prognosis, now that more intensive treatment regimens are used for patients with this subtype, this difference is no longer observed.