Precursor B- and T-Cell Neoplasms

Definition

B-cell ALL/LBL is a clonal disorder of hematopoietic precursors with evidence of early B-cell differentiation. The disease is characterized by the presence of a rapidly proliferating population of immature blasts, with minimal morphologic evidence of differentiation. Defining these tumors generally requires immunophenotypic demonstration of B-cell lineage antigen expression. For example, more than 95% of cases express CD19 and HLA-DR. Further, nearly all show clonal rearrangement of the immunoglobulin heavy-chain gene.

Epidemiology

ALL is the most common malignancy in children. It accounts for 80% of childhood leukemias but only about 20% of adult acute leukemias. Most cases occur in children younger than 6 years, with the majority being B-cell ALL. The peak incidence is approximately 4 to 5 cases per 100,000 between 2 and 5 years of age; the incidence decreases thereafter until 50 years of age, when it begins to climb slightly again. ALL affects whites and Hispanics more commonly than blacks, and Hispanic children have a higher incidence of ALL and a higher relapse rate than white children. B-cell LBL is less common than T-cell LBL, accounting for only about 10% of LBLs. B-cell LBL is also a disease of young individuals, with the majority of cases occurring in those younger than 20 years.

Etiology

The etiology of B-cell (and T-cell) ALL is unknown. A number of studies have suggested a prenatal origin of the genetic events predisposing to the development of leukemia; others have demonstrated the presence of clone-specific antigen receptor gene rearrangements in infants, consistent with an in utero origin of at least a portion of childhood ALLs. Further, identical leukemia-specific translocations and antigen receptor gene rearrangements have been documented in monozygotic twins with B-cell ALL. However, these findings are thought to represent somatic mutations occurring in one twin and shared via in utero circulation rather than constitutional genetic lesions. Although the specific genetic and environmental factors that predispose to ALL are not well defined, certain factors, such as exposure to ionizing radiation, and certain genetic diseases, such as Down syndrome and ataxia-telangiectasia, have been associated with the development of ALL. Recent studies have also shown that single-nucleotide polymorphisms (SNPs) of several genes, including GATA3, ARID5B, IKZF1, CEBPE, and CDKN2A/B, are associated with susceptibility to B-cell ALL. Disease in these patients has a relatively poor outcome, and a disproportionate percentage are adolescents and young adults. One of these SNPs (rs3824662) is more common in Hispanics and has been suggested to account, in part, for the poorer outcomes seen in this group relative to whites. However, true familial ALL is rare, with kindreds described having mutations in PAX5 , ETV6 , and TP53 . Also, rare cases of ALL following chemotherapy have been documented; these often possess rearrangements or amplification of the homeotic regulator mixed lineage leukemia (MLL) gene (now called KMT2A ) on chromosome 11q23.

Clinical Features

The typical clinical presentation of B-cell ALL ( Box 42-1 ) relates to the development of cytopenias secondary to the replacement of normal bone marrow by leukemic blasts. Clinical manifestations include weakness and pallor due to anemia, petechiae, and bruising secondary to thrombocytopenia, and fever despite granulocytopenia. It is important to note that ALL patients may present with low, normal, or elevated peripheral white blood cell counts. Thus, patients with unexplained pancytopenia may warrant a bone marrow examination to exclude leukemia. In addition, hepatosplenomegaly or lymphadenopathy may be present at diagnosis, and there may be organ dysfunction due to leukemic infiltration. Bone or joint pain is also common, particularly in children, and is due to intramedullary growth of the leukemic cells. B-cell LBL typically presents with skin or lymph node involvement with or without peripheral blood or bone marrow involvement, and there have also been rare reports of B-cell LBL presenting as lytic bone lesions. In contrast to T-cell LBL, B-cell LBL rarely involves the mediastinum.

Morphology

The morphologic examination of peripheral blood or bone marrow remains an essential part of the ALL diagnosis. Blasts in B-cell ALL can be heterogeneous. Previous classification schemes attempted to subdivide ALL on the basis of cytologic features, including nuclear-to-cytoplasmic ratio, nucleoli, nuclear membrane contours, and cell size. However, aside from distinguishing the more mature Burkitt's leukemia/lymphoma (previously considered ALL, L3 ) from precursor B-cell ALL, subdividing ALL on the basis of morphology alone has little prognostic value and has been supplanted by immunophenotypic, cytogenetic, and molecular subclassification. Nevertheless, recognition of lymphoblasts is important to initiate the appropriate diagnostic evaluation. On a peripheral blood or bone marrow smear, lymphoblasts range from small, round blasts with high nuclear-to-cytoplasmic ratios, relatively condensed chromatin, and inconspicuous nucleoli to larger cells with an increased amount of blue-gray to blue cytoplasm, irregular nuclei with dispersed chromatin, and variably distinct nucleoli. Cytoplasmic vacuoles may be present; this finding does not automatically indicate Burkitt's leukemia/lymphoma.

Several morphologic variants of B-cell ALL have been described. The first, the so-called hand-mirror–cell leukemia, displays a distinctive morphology characterized by the presence of an asymmetric cytoplasmic projection called a uropod, which typically sits atop an umbilicated nucleus. Although the cause of this unusual morphology is uncertain, it has been suggested that immune complexes contribute to the formation of uropods. The presence of hand-mirror cells does not appear to be associated with any particular subtype of ALL, nor does it independently affect prognosis. The second, less common morphologic variant is granular ALL. In this disorder, the blasts contain azurophilic cytoplasmic granules that do not contain myeloperoxidase but can contain acid phosphatase or acid esterase activity, suggesting a lysosomal origin. These cases may not show the increased right angle side scatter seen in flow cytometry analysis of myeloid blasts that contain abundant granules. Rarely, cases of B-cell ALL may be associated with peripheral blood eosinophilia that is so marked that it obscures the lymphoblasts, although the lymphoblasts themselves are not morphologically distinctive. Although the eosinophils are not part of the neoplastic clone, patients with ALL and eosinophilia often have symptoms related to the toxic effects of eosinophil degranulation, particularly cardiac disease. This unusual manifestation is often associated with the chromosomal abnormality t(5;14)(q31-33;q32), which juxtaposes the interleukin-3 (IL3) gene with the immunoglobulin heavy-chain (IGH) gene on chromosome 14.

The histopathologies of B-cell ALL and LBL are indistinguishable, and the distinction is based on the distribution of tissue involvement. In ALL the bone marrow is almost always hypercellular, with replacement of normal marrow elements by a diffuse infiltrate of immature cells ( Fig. 42-1 ). High-power examination reveals morphologic heterogeneity similar to that observed on smear preparations, ranging from small blasts with fine chromatin and inconspicuous nucleoli to more heterogeneous cells with irregular nuclei and more abundant cytoplasm. Occasionally, tingible body macrophages accompany the infiltrate, imparting a “starry sky” appearance; however, the tingible body macrophages are usually not as abundant as in Burkitt's lymphoma and may occur only focally. With B-lineage ALL, there can be significant organ involvement, with the liver, spleen, kidneys, gonads, and central nervous system (CNS) being common sites. B-cell LBL is diagnosed when there is an extramedullary tumor of lymphoblasts but less than 25% lymphoblasts in the blood or bone marrow. It is found most often in extranodal sites, most commonly skin or bone. Lymph nodes are less commonly involved and may demonstrate a paracortical distribution, with preservation of follicles. Hepatic involvement is typically sinusoidal, whereas splenic disease involves the red pulp.

Immunophenotype

B-cell ALL is defined by evidence of B-cell differentiation. Normal precursor B cells exist in variable numbers in the bone marrow. These undergo a reproducible pattern of antigen expression during normal B-cell differentiation. In contrast, B-cell ALL almost always demonstrates an aberrant antigen profile that is incompatible with normal B-cell differentiation, thus permitting a distinction between malignant and reactive precursor B cells. Nearly all cases of B-cell ALL express CD19, cytoplasmic CD79a, terminal deoxynucleotidyl transferase (TdT), and HLA-DR. CD10 is present in most, but not all, cases. Surface expression of CD22 is weak but consistent. CD20 is usually variably expressed, although individual cases can range from complete absence of CD20 to moderately intense and uniform expression of this antigen. Cytoplasmic CD22 is a very sensitive marker for B-cell ALL, but it may also be detected in acute myeloid leukemia (AML) in conjunction with possible weak expression of CD19 and TdT. CD79a has been suggested as both a sensitive and a specific marker of B-lineage ALL, but it is also seen in a significant fraction of T-cell ALL/LBLs. PAX5 is more specific than CD79a, although it may be seen in some cases of AML. Although immunoglobulin heavy-chain gene rearrangements occur relatively early in B-cell development, and B-cell ALLs show clonal rearrangements by molecular analysis, most fail to express surface immunoglobulin.

Additional antigenic markers have been useful in characterizing B-lineage ALL, with emphasis placed on those that are suitable for distinguishing normal and leukemic precursors. These include CD24, CD34, and CD9, all of which are expressed in the majority of cases. It should be noted that among B-cell neoplasms, CD34 is uniquely expressed in lymphoblastic lesions and has particular significance in classifying these lesions. TdT expression is also characteristic of immature B-lymphoblastic lesions, although it has been very rarely reported in B-cell lymphoma, unclassifiable, with features intermediate between large B-cell lymphoma and Burkitt's lymphoma. CD45, or the leukocyte common antigen, is not expressed in approximately 10% to 20% of cases of B-cell ALL and typically shows considerable variability in expression in the remaining cases. CD99, more commonly thought of as a marker of Ewing's sarcoma, is also expressed by most hematopoietic tumors that express TdT. Thus, expression of CD99 coupled with lack of CD45 expression does not exclude LBL. Finally, expression of myeloid antigens, including CD13, CD33, and CD15, is found in about 10% to 15% of childhood B-cell ALLs and in approximately 25% of adult cases. However, the myeloid-blast–associated antigen CD117 is only very rarely present in B-cell ALL and should prompt consideration of a B/myeloid mixed-phenotype acute leukemia (MPAL). The routine evaluation for myeloperoxidase (MPO) expression in B-cell ALL can be problematic because otherwise typical cases of B-cell ALL have occasionally been shown to express low levels of MPO, and this should not automatically result in a diagnosis of MPAL in the absence of other criteria.

Several distinct clinical subgroups of B-cell ALL are accompanied by unique patterns of antigen expression. Some of these are associated with distinct molecular or cytogenetic defects and have distinct clinical characteristics ( Table 42-1 ). For example, pre–B-cell ALL is distinguished from other B-cell ALLs by the expression of cytoplasmic immunoglobulin mu heavy chain without surface immunoglobulin. About 25% of cases of pre–B-cell ALL harbor a specific (1;19) translocation, which is discussed in more detail later. Transitional pre–B-cell ALL is another distinct immunologic subset of B-cell ALL, with differentiation characteristics that are intermediate between pre–B-cell ALL and Burkitt's leukemia/lymphoma. In transitional pre–B-cell ALL, surface immunoglobulin mu heavy chain is expressed, but immunoglobulin light chain is not. This neoplasm lacks the typical L3 morphology of Burkitt's leukemia/lymphoma and does not possess translocations involving the MYC oncogene. It also possesses the immature markers CD34 and TdT, which are usually absent in more mature B-cell leukemias. These tumors must be distinguished from Burkitt's leukemia/lymphoma because they respond well to ALL-type therapy. In addition, rare cases of ALL with non-L3 morphology express both immunoglobulin heavy chain and light chain and lack the MYC translocation characteristic of Burkitt's leukemia/lymphoma. Although there have been no systematic studies of this rare subgroup, in practice, such patients are treated similarly to other B-cell ALL patients.

Genetics and Molecular Findings

Nearly all cases of B-cell ALL have rearrangement of the immunoglobulin heavy-chain gene. However, immunoglobulin heavy-chain gene rearrangement can also occur in T-cell ALL as well as in AML, limiting the utility of this test as a marker of lineage commitment. Immunoglobulin light-chain rearrangement can also occur and is thought to be a more specific marker of B-cell differentiation. Unlike the more mature B-cell lymphoproliferative disorders, translocations activating oncogenes in B-cell ALL rarely involve immunoglobulin loci.

B-lineage ALL is increasingly being defined by specific genetic abnormalities associated with specific phenotypes and clinical behaviors. Most of these are incorporated into World Health Organization's classification of B-cell ALL in the fifth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues ( Box 42-2 ). Risk stratification may be used to identify patients for whom low-intensity therapy will likely be curative, thus avoiding complications of more aggressive treatment, and it can also be used to identify patients needing more intensive therapy. Moreover, as epitomized by ALL with BCR - ABL1, some of the genetic abnormalities may provide clues leading to specific targeted therapy. Thus, it is useful to consider these common recurrent chromosomal and molecular abnormalities individually.