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Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma

Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma
Authors:
Anjali S Advani, MD
Jon C Aster, MD, PhD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 27, 2022.

INTRODUCTION — The lymphoblastic neoplasms are classified on the basis of B cell versus T cell lineage [1]:

B cell lymphoblastic leukemia/lymphoma (B cell ALL/LBL)

T cell lymphoblastic leukemia/lymphoma (T cell ALL/LBL)

Leukemia and lymphoma are overlapping clinical presentations of the same disease (ie, B cell ALL/LBL); diagnosis and classification do not distinguish between these entities.

B cell ALL/LBL was formerly called pro-B lymphoblastic leukemia; common precursor B-lymphoblastic leukemia; pre-B lymphoblastic leukemia; pre-pro-B lymphoblastic leukemia; common lymphoblastic leukemia; precursor B cell lymphoblastic lymphoma; precursor B cell lymphoblastic leukemia, NOS; and B cell acute lymphoblastic leukemia.

Epidemiology, clinical presentation, and diagnosis of B cell ALL/LBL is discussed here.

The following topics are discussed separately:

Treatment of B cell ALL/LBL (see "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults" and "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents")

Diagnosis and management of T cell ALL/LBL (see "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma" and "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults")

EPIDEMIOLOGY — The estimated annual incidence of acute lymphoblastic leukemia (ALL) worldwide is 1 to 5 cases/100,000 population, and more than two-thirds of cases of ALL are B cell phenotype [2,3].

B cell ALL/LBL is primarily a disease of children, with three-quarters of cases occurring in children <6 years old; there is a second peak of incidence in adults >60 years old [2,3]. B cell ALL occurs slightly more frequently in males than females. The incidence of B cell ALL/LBL is three times higher in White people than Black people. Hispanic populations have the highest incidence of any ethnic group, and the incidence appears to be increased in certain areas of Central and South America (eg, Guatemala, Peru), for unknown reasons [4]. The Philadelphia-like signature (discussed below) is also significantly more common in patients of Hispanic ethnicity [5]. (See 'BCR::ABL1-like (Ph-like)' below.)

The cause of B cell ALL/LBL is unknown, but it may be associated with ionizing radiation and/or as-yet unidentified infectious agents [6]. True familial ALL is rare, although it has been associated with inherited mutations of PAX5, ETV6, and TP53 [7,8]. There is an increased incidence of B cell ALL in children with Down syndrome and other constitutional disorders [9]. B cell ALL/LBL is also associated with certain single nucleotide polymorphisms in specific genes, including GATA3, ARID5B, IKZF1, CEBPE and CDKN2A/B [10,11]. (See "Familial disorders of acute leukemia and myelodysplastic syndromes" and "Down syndrome: Clinical features and diagnosis", section on 'Hematologic disorders'.)

CLINICAL FEATURES — B cell lymphoblastic leukemia and B cell lymphoblastic lymphoma are overlapping clinical manifestations of the same disease.

Most patients have findings associated with anemia, neutropenia, and/or thrombocytopenia due to bone marrow involvement. The white blood cell count may be decreased, normal, or markedly elevated. Symptoms can include fatigue, infections, or easy/spontaneous bruising or bleeding. Bone pain or arthralgias may be prominent complaints, and constitutional symptoms (eg, fever, night sweats, unintentional weight loss) are often present, but are generally mild. Hepatomegaly, splenomegaly, and/or lymphadenopathy are present in up to half of adults. Central nervous system (CNS) involvement may be manifest as cranial neuropathies or meningeal symptoms.

The tempo of disease is variable; some patients present with symptoms that progress slowly over weeks to months, while others have a more acute presentation.

A study of 53 children with B cell LBL who were enrolled on clinical trials reported the following presenting features: osteolytic bone lesions (26 percent), skin or subcutaneous lesions (23 percent), mediastinal or pleural disease (11 percent), bone marrow (13 percent), lymph nodes alone (13 percent), gonads (6 percent), head and neck (4 percent), or kidney and digestive system (2 percent each); in addition, 43 percent had bone marrow involvement and 6 percent had CNS involvement [12].

Specific cytogenetic/genetic categories are associated with distinctive clinical presentations, as described below. (See 'Classification of B cell ALL/LBL' below.)

PATHOLOGIC FEATURES

Morphology — The blood smear reveals lymphoblasts that may vary from small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli (picture 1) to larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli [13]. Children more commonly have smaller blasts, while adults more commonly have larger blasts [13]. A few azurophilic cytoplasmic granules may be present, but Auer rods are absent.

In tissue sections, the tumor cells are small to medium-sized with uniform appearance and scant cytoplasm (picture 2 and picture 3); occasional cases have larger lymphoblasts. Nuclei are oval or convoluted with finely dispersed chromatin and indistinct or small nucleoli.

Cytochemistry — Although not required to establish the diagnosis, characteristic cytochemical findings in B cell ALL/LBL are:

Periodic acid-Schiff (PAS) – Lymphoblasts may reveal coarse ("chunky") granules due to the presence of glycogen

Nonspecific esterase (NSE) – Multifocal punctate or Golgi region pattern of staining, typically much weaker than in acute myeloid leukemias with monocytic differentiation

Sudan black B – Variable positivity

Myeloperoxidase (MPO) – No staining

Flow cytometry/immunohistochemistry — Immunophenotype, defined by flow cytometry and/or immunohistochemistry from circulating lymphoblasts, bone marrow specimen, or lymph node material, is required for the diagnosis of B cell ALL/LBL. (See 'Evaluation and diagnosis' below.)

An essential characteristic of B cell ALL/LBL is expression of B cell antigens with absence of T cell antigens; in some cases, myeloid antigens may be expressed:

B cell antigens - Lymphoblasts of B cell ALL/LBL are almost always positive for the B cell markers CD19, cytoplasmic CD79a, and cytoplasmic CD22; none of these markers alone is specific to the diagnosis, but their positivity in combination or at high intensity strongly supports the diagnosis [1]. In most cases, lymphoblasts are also positive for CD10, CD24, PAX5, and TdT (terminal deoxytransferase); CD20 and CD34 expression is variable, and CD45 may be absent or dim. CD20 expression is present in approximately 40 to 50 percent of B cell ALL cases [14].    

T cell antigens – T cell antigens (eg, CD3) are negative.

Myeloid antigens – Myeloid antigens, such as CD13 and CD33, may be expressed and do not exclude the diagnosis of B cell ALL/LBL; however, expression of myeloperoxidase (MPO) is considered myeloid lineage-defining and excludes the diagnosis [1].

Expression of CD13 and/or CD33 is associated with particular categories of B cell ALL/LBL (eg, ETV6::CBFA2, KMT2A, BCR::ABL1), as described below. (See 'Classification of B cell ALL/LBL' below.)

Characteristic flow cytometry (figure 1) and immunohistochemistry (for TdT) for B cell ALL/LBL are illustrated (picture 4).

Cytogenetic/Molecular analysis — Conventional chromosomal banding, with or without fluorescence in situ hybridization (FISH), and molecular analysis (for gene rearrangements and patterns of gene expression) should be performed on circulating lymphoblasts, a bone marrow specimen, and/or lymph node material for the classification of B cell ALL/LBL. Fluorescence in situ hybridization (FISH) for t(12;21) can be important, since this rearrangement may be difficult to recognize by karyotyping. Given that the presence of KMT2A and BCR::ABL1 fusion genes can dictate prognosis and treatment decisions, FISH testing should be performed for these abnormalities. (See "General aspects of cytogenetic analysis in hematologic malignancies" and 'Classification of B cell ALL/LBL' below.)

Testing should also be performed to detect BCR::ABL1-like ALL, ideally by gene expression profiling. Alternative approaches (eg, low-density array [LDA] screening, flow cytometry for CRLF2 overexpression, or detection of fusion genes associated with BCR::ABL1-like ALL by cytogenetics/FISH or RNA sequencing) can also be used to identify many cases of BCR::ABL1-like ALL [5,15]. If it is not possible to do this testing in house, send out testing should be performed given the impact of this subtype on prognosis and treatment decisions. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'BCR::ABL1-like B cell ALL'.)

Rearrangement of antigen receptor genes in B cell ALL/LBL is variable and not lineage-specific; as a result, detection of such rearrangements is not a reliable method for assigning lineage. Nearly all cases of B cell ALL have rearrangements of immunoglobulin heavy chain (IGH), but up to 70 percent of cases also have rearrangements of the T cell receptor (TCR) gamma or beta chain genes [16-18].

EVALUATION AND DIAGNOSIS — B cell ALL/LBL is usually suspected in a child or adult with circulating lymphoblasts and/or painless lymphadenopathy, and may be suspected in the setting of unexplained cytopenias; fatigue, infections, easy or spontaneous bruising/bleeding; constitutional symptoms; bone pain; and/or hepatomegaly or splenomegaly. (See 'Clinical features' above.)

Evaluation should include a complete blood count with differential, examination of the peripheral smear, immunophenotype of peripheral blood or marrow, and bone marrow examination; in some cases, evaluation may include an excisional or needle core biopsy of a lymph node [1]. (See 'Pathologic features' above.)

This material should also be analyzed by cytogenetic and molecular techniques to enable categorization according to the World Health Organization (WHO) classification [1] (table 1). (See 'Classification of B cell ALL/LBL' below.)

Diagnosis of B cell ALL/LBL requires detection of lymphoblasts with the characteristic immunophenotype in peripheral blood, bone marrow, or other involved tissue; although there is no consensus regarding a minimal proportion of lymphoblasts in bone marrow, the diagnosis of B cell ALL/LBL should be avoided when there are <20 percent lymphoblasts [1].

Following is the characteristic immunophenotype of B cell ALL/LBL:

B cell antigens - Lymphoblasts of B cell ALL/LBL are almost always positive for CD19, cytoplasmic CD79a, and cytoplasmic CD22; none of these markers alone is specific to the diagnosis, but their positivity in combination or at high intensity strongly supports the diagnosis [1].

T cell antigens – T cell antigens (eg, CD3) are negative.

Myeloid antigens – Myeloid antigens, such as CD13 and CD33, may be expressed and do not exclude the diagnosis of B cell ALL/LBL [1]. However, expression of myeloperoxidase (MPO) is considered myeloid lineage-defining, and coexpression of MPO with B lineage antigens excludes the diagnosis of B cell ALL/LBL.

DIFFERENTIAL DIAGNOSIS — Diagnosis of B cell ALL/LBL is described above. (See 'Evaluation and diagnosis' above.)

The differential diagnosis includes malignant and nonmalignant processes.

Malignant disorders — Immunophenotype and cytogenetic/molecular findings are necessary to distinguish B cell ALL/LBL from other leukemias and lymphomas, because morphology alone is not diagnostic.

T cell ALL/LBL — Immunophenotyping is required to distinguish T cell ALL/LBL from B cell ALL/LBL. Rearrangement of antigen receptor genes (ie, immunoglobulin [Ig] genes, T cell receptors) is not entirely lineage specific and cannot be used to distinguish between these disorders, as described above. (See 'Cytogenetic/Molecular analysis' above.)

Lymphoblasts of T cell ALL/LBL are typically positive for CD7 and either surface or cytoplasmic CD3; other immunophenotypic characterization of T cell ALL/LBL is discussed separately. Cytogenetic and molecular features of T cell ALL/LBL also are almost entirely different from B cell ALL/LBL. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Evaluation and diagnosis'.)

T cell ALL/LBL is more likely to be associated with a mediastinal mass; other aspects of the clinical presentation are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Clinical presentation'.)

Burkitt lymphoma — Typically, the malignant cells of Burkitt lymphoma (BL) have a somewhat different appearance from lymphoblasts in smears, but there is sufficient overlap that this distinction cannot be made reliably, particularly in cases of BL with extensive marrow involvement.

The diagnosis of BL is based on morphology, immunophenotype, and cytogenetic/molecular features of blood, bone marrow, lymph node, or other tissue. Histology reveals a monomorphic collection of medium-sized cells with basophilic cytoplasm and a high proliferation fraction (often with a "starry sky" appearance and Ki-67+ fraction approaching 100 percent). Compared with B cell ALL/LBL, the malignant cells of BL are generally larger (ie, intermediate-sized oval or round nuclei, dispersed chromatin, several distinct nucleoli, and abundant cytoplasm). Diagnosis of BL relies on immunophenotype (typically a mature germinal center B cell phenotype: CD19+, CD20+, CD10+, surface Ig positive) and detection of a translocation involving chromosome 8q24 and/or MYC rearrangement. By contrast, B lymphoblasts do not express surface Ig and are variably positive for CD10 and CD20.

Rarely, Burkitt lymphoma may express TdT, and a small subset of B cell ALL/LBL has MYC rearrangements. It is usually possible to distinguish between these two tumors based on immunophenotyping, as Burkitt lymphoma has a mature B cell phenotype and expresses surface light chain, whereas B cell ALL/LBL lacks these features.

Diagnosis of BL is discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Diagnosis'.)

Other acute leukemias — B cell ALL/LBL lymphoblasts may be difficult to distinguish morphologically from other forms of acute leukemia, particularly those that are minimally differentiated:

Acute myeloid leukemia (AML) – Myeloblasts of AML are immature cells with large nuclei, usually with prominent nucleoli, and a variable amount of pale blue cytoplasm (sometimes with faint granulation and/or Auer rods). AML cells generally stain for myeloperoxidase (MPO) or lysozyme and are generally negative for B and T cell antigens and TdT. Exceptions to this rule are recognized; as an example, AML associated with t(8;21) characteristically expresses PAX5 and CD19 [19] and has been reported to respond to therapy directed against CD19 [20]. Other aspects of the diagnosis of AML are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)

Acute undifferentiated leukemia (AUL) – AUL blast cells are morphologically bland and generally indistinguishable from those of B cell ALL/LBL. Distinguishing between these entities depends on immunophenotyping. AUL blasts do not express lineage-specific antigens by flow cytometry or immunohistochemistry; in contrast, B cell ALL/LBL blasts express B lymphoid antigens (and may also express certain myeloid antigens). There is no cytogenetic or molecular finding that is specific for these leukemias. (See "Mixed phenotype acute leukemia", section on 'Acute undifferentiated leukemia'.)

Mixed phenotype leukemia (MPAL) – Diagnosis of MPAL requires demonstration of both myeloid- and lymphoid-defining markers by flow cytometry and/or immunohistochemistry and the absence of entity-defining genetic aberrations, such as t(8;21). (See "Mixed phenotype acute leukemia", section on 'Diagnostic evaluation'.)

Other lymphoproliferative disorders — Other lymphoproliferative disorders that may resemble B cell ALL/LBL clinically and/or morphologically can be distinguished by immunophenotype and/or genetic features, including:

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) – CLL/SLL is distinguished from B cell ALL/LBL by a preponderant population of morphologically mature-appearing small lymphocytes with appropriate immunophenotype (expression of B cell antigens CD19, CD20, and CD23; T cell antigen CD5; and low-level monoclonal surface immunoglobulin) in peripheral blood (≥5000/microL) or lymph node, spleen, or other extramedullary tissue. On occasion, a preponderance of small blasts in B cell ALL/LBL may result in a superficial morphologic resemblance to CLL/SLL, but other features cited above readily distinguish these entities. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Evaluation and diagnosis'.)

B prolymphocytic leukemia (PLL) – PLL is distinguished from B cell ALL/LBL by detection of characteristic prolymphocytes (ie, light chain restriction, bright surface immunoglobulin, expression of B cell antigens CD20, CD22, FMC7, CD79a; absent or weak CD5 and CD23 expression; and no expression of CD11c, CD103, CD10, and CD25) that constitute >55 percent of lymphoid cells in the peripheral blood. (See "B cell prolymphocytic leukemia", section on 'Diagnosis'.)

Mantle cell lymphoma (MCL) – MCL is distinguished from B cell ALL/LBL by the characteristic histologic appearance (eg, small to medium-sized lymphoid cells, with slightly irregular or "notched" nuclei), immunophenotype (typically expressing CD19, CD20, CD5, and FMC7), nuclear staining for cyclin D1 (BCL1), and t(11;14)(q13;q32) or CCND1-IgH rearrangement. On occasion, blastoid variants of MCL may closely mimic the morphologic appearance of B cell ALL/LBL, but these entities are readily distinguish by the other criteria cited above. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma", section on 'Diagnosis'.)

Plasma cell leukemia – Plasma cell leukemia may sometimes be composed of relatively small, blast-like cells, but is distinguished from B cell ALL/LBL by its characteristic immunophenotype (eg, positive for CD79a, VS38c, CD138, and CD38) in peripheral blood, bone marrow, or extramedullary tissue, and the presence of monoclonal serum immunoglobulin and/or free light chains. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis' and "Plasma cell leukemia".)

Chronic myeloid leukemia (CML) in blast crisis — Morphologically, CML is typically manifested as an expanded population of myeloid cells at various stages of differentiation with the Philadelphia chromosome, t(9;22), and BCR::ABL1 rearrangement. About 10 percent of blast crisis CML may have a dominant population of lymphoblasts, but in this setting, the Philadelphia chromosome is detected in myeloid cells and basophilia may be present. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Diagnosis'.)

Small round blue cell tumors — In children, small round blue cell tumors, including Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumor (PNET) may resemble B cell ALL/LBL morphologically, but these disorders are distinguished by a uniform population of small, round, blue cells with hyperchromatic nuclei and scant cytoplasm; absence of B lymphoid markers; and presence of certain characteristic cytogenetic/molecular findings (eg, t(11;22)(q24;q12), EWSR1::FLI1 rearrangement). Diagnosis of small round blue cell tumors and the differential diagnosis of such tumors are discussed separately. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Differential diagnosis'.)

Nonmalignant disorders — Certain nonmalignant disorders may resemble B cell ALL/LBL morphologically and/or clinically. In adults and children, the following disorders may be included in the differential diagnosis:

Human immunodeficiency virus (HIV)

Infectious mononucleosis

Pertussis

Osteomyelitis

Tuberculosis

Heavy metal toxicity

Thymoma

Autoimmune diseases (including juvenile rheumatoid arthritis in children)

Distinguishing these disorders from B cell ALL/LBL in children and adults is discussed separately. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Causes of reactive lymphocytosis' and "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Causes of lymphocytosis'.)

In infants and very young children, the differential diagnosis also includes hematogones, which are normal developing pre-B cells in peripheral blood or bone marrow. Hematogones show a spectrum of B lymphocyte maturation, including surface immunoglobulin light chain, and display a reproducible pattern of acquisition and loss of normal B cell antigens. In contrast, most malignant cells in B cell ALL/LBL have a single immunophenotype and the spectrum of normal B cell differentiation is absent. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Malignant lymphocytosis'.)

CLASSIFICATION OF B CELL ALL/LBL — All cases of B cell ALL/LBL should be categorized according to the immunophenotypic and cytogenetic/genetic classification described in the sections that follow. Additional discussion of classification of B cell ALL/LBL is presented separately.(See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

It is not necessary to distinguish between leukemia versus lymphoma, because they are considered different clinical manifestations of the same disease.

B cell ALL/LBL, NOS — B cell ALL/LBL, not otherwise specified (NOS) has none of the features that define the various cytogenetic/genetic categories that are described below.

Typical clinical presentation, pathologic features, and diagnosis of B cell ALL/LBL NOS are described above. (See 'Clinical features' above and 'Pathologic features' above and 'Evaluation and diagnosis' above.)

Ph+; t(9;22)(q34.1; q11.2); BCR::ABL1 — The Philadelphia (Ph) chromosome, t(9;22), is associated with expression of the BCR::ABL1 oncogene. Although Ph+ ALL was historically considered an adverse feature, its prognostic importance has improved in the era of tyrosine kinase inhibitors [21].

Ph is detected in approximately one-quarter of adult ALL, but in only 2 to 4 percent of childhood cases; the incidence increases with age, and it is found in 40 to 50 percent of patients ≥60 years old [22-24].

Ph+ B cell ALL/LBL is defined by chromosomal banding, fluorescence in situ hybridization (FISH), and/or detection of BCR::ABL1 by RT-polymerase chain reaction; approximately one-half of cases express the p210 BCR::ABL1 protein (characteristic of chronic myeloid leukemia) and half express the p190 protein [25]. Ph+ B cell ALL/LBL is often associated with a pre-B immunophenotype (CD19+, CD10+); it is typically positive for TdT and CD25, and there is frequent expression of myeloid antigens [26-29]. However, no specific morphologic or clinical features distinguish Ph+ B cell ALL/LBL from other categories.

The distinctive management of Ph+ B cell ALL/LBL is discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults" and "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

t(v;11q23.3); KMT2A-rearranged — This category of B cell ALL/LBL harbors t(v;11q23.3) and a translocation involving KMT2A (formerly called MLL) with one of >100 fusion partners including AFF1 (AF4), MLLT1 (ENL), or MLLT3 (AF9).

This is the most common category of B cell ALL in infants; it is less common in older children, but it becomes increasingly common in adulthood [1]. The white blood cell (WBC) count is typically increased, frequently >100,000/microL. Central nervous system (CNS) involvement is common and there may be infiltration of other organs, although pure lymphomatous presentations are not typical.

KMT2A-rearranged tumors typically manifest a pro-B immunophenotype (CD19+, CD10-), often with co-expression of the myeloid markers CD15, CD33, and CD68 [26,30]. FISH may be required to diagnose this subtype, as some rearrangements are cytogenetically cryptic [31].

Leukemias with deletion of 11q23.3 without KMT2A rearrangement are not included in this category. Cases of acute leukemia with KMT2A rearrangement and distinct lymphoblastic and monoblastic populations (by morphology and/or immunophenotyping) should be considered mixed phenotype acute leukemia, as described below. (See 'Other acute leukemias' above.)

B cell ALL with KMT2A rearrangement is associated with a poor prognosis [27,32]. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Structural abnormalities'.)

t(12;21)(p13.2;q22.1); ETV6::RUNX1 — This category of B cell ALL/LBL is associated with t(12;21) and the ETV6::CBFA2 fusion (formerly known as TEL::AML1).

This subtype is the most common form of B cell ALL/LBL associated with a defining chromosomal rearrangement in children (approximately one-quarter of cases); it is not seen in infants and it is rare in adulthood [6,33].

These tumors usually have a pre-B cell immunophenotype (CD19+, CD10+). Absent or dim expression of CD9, CD20, and CD66c is relatively specific for this entity [28,34,35]. The malignant cells are usually CD34+, and they frequently express myeloid-associated antigens (especially CD13) [36]. This form of B cell ALL/LBL is associated with a unique gene expression signature [37]. FISH may be required to detect this disorder, as some rearrangements are cytogenetically cryptic [38].

B cell ALL/LBL t(12;21)(p12;q22);ETV6::CBFA2 is associated with a good prognosis. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Structural abnormalities'.)

Hyperdiploidy — Hyperdiploid B cell ALL/LBL has >50 chromosomes, typically without translocations or other structural chromosomal alterations. Hyperdiploid B cell ALL can be detected by conventional karyotyping, FISH, or flow cytometric DNA index [39].

Hyperdiploid B cell ALL is common in children (≥25 percent of childhood cases), it is not seen in infants, and its frequency decreases among older children. It is uncommon in adulthood (7 to 8 percent) of B cell ALL [40].

Hyperdiploid B cell ALL/LBL has no distinguishing morphologic or clinical features. The lymphoblasts have a pre-B cell immunophenotype (CD19+, CD10+) and in most cases are CD34+; CD45 is often absent [28]. Chromosomes 21, X, 14, and 4 most commonly show increases in copy number [41].

The prognostic significance in adults is uncertain, but hyperdiploid B cell ALL has a very favorable prognosis in children. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'High hyperdiploidy'.)

Hypodiploidy — Hypodiploid B cell ALL/LBL is characterized by loss of one or more chromosomes.

About 5 percent of cases of B cell ALL/LBL are hypodiploid, but only 1 percent have <45 chromosomes [42]. The incidence of hypodiploidy is higher in adults.

The lymphoblasts of hypodiploid B cell ALL/LBL have a pre-B cell immunophenotype (CD19+, CD10+), but there are no other distinctive immunophenotypic or clinical features.

Hypodiploid B cell ALL cases may be subclassified based on the number of chromosomes into categories with distinctive genetic lesions: near-haploid (23 to 29 chromosomes), low hypodiploid (33 to 39), high hypodiploid (40 to 43), and near-diploid (44 to 46); As examples, near-haploid B cell ALL often has RAS or receptor tyrosine kinase mutations, while most low hypodiploid B cell ALL have loss-of-function mutations of TP53 and/or RB1.

Near-diploid classes are associated with a good prognosis, but all other classes of hypodiploid B cell ALL/LBL are associated with a poor prognosis [42]. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Hypodiploidy'.)

t(5;14)(q31.1;q32.1); IGH::IL3 — In this category, lymphoblasts harbor a translocation between IL3 and IGH (immunoglobulin heavy chain).

This rare disorder accounts for <1 percent of cases of B cell ALL, and it has been reported in both children and adults [1].

The form of B cell ALL/LBL is often associated with low numbers of circulating lymphoblasts accompanied by asymptomatic eosinophilia; the eosinophils are a reactive population of cells and not part of the malignant clone. Even small numbers of CD19+, CD10+ blasts in a patient with eosinophilia strongly suggests this diagnosis [1].

The rearrangement between IL3 on chromosome 5 and IGH on chromosome 14 causes constitutive overexpression of IL3 [43].

Prognosis is not considered to be different from other categories of B cell ALL [44].

t(1;19)(q23;p13.3); TCF3-PBX1 — The presence of t(1;19) translocation and/or fusion of TCF3 (also known as E2A) and PBX1 defines this category. TCF3::PBX1 translocation generates a fusion protein that acts as a transcriptional activator and also interferes with function of normal TCF3 and PBX1 [45].

This cytogenetic/genetic abnormality is relatively common in children (approximately 6 percent of B cell ALL), but it is less common in adults [6].

Lymphoblasts typically have a pre-B phenotype and are CD19+, CD10+, CD9+, express cytoplasmic Mu heavy chain, and are dim or negative for CD34 [46]. This category has no unique morphologic or clinical aspects, but does have a distinct gene expression profile signature [37]. There may be an increased risk of CNS relapse in these patients [47].

The category of B cell ALL/LBL t(1;19)(q23;p13.3); TCF3::PBX1 has no distinctive prognostic significance with contemporary treatment. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Structural abnormalities'.)

Demonstration of a TCF rearrangement alone is not sufficient to diagnose this category of leukemia, because an alternative translocation of TCF3 that involves the HLF gene is associated with t(17;19) and is associated with a dismal prognosis [1].

BCR::ABL1-like (Ph-like) — This category is associated with a gene expression signature that resembles that of Ph+ B cell ALL, but the cells lack the characteristic (9;22) translocation and associated BCR::ABL1 fusion gene [15].

The BCR::ABL1-like category accounts for approximately 10 percent of childhood B cell ALL/LBL, but up to one-third of cases in adults [6,48]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'BCR::ABL1-like B cell ALL'.)

Patients with BCR::ABL1-like B cell ALL/LBL tend to have a high WBC count at presentation. Lymphoblasts have a CD19+, CD10+ phenotype. Cases with CRLF2 translocations show high level expression of surface CRLF2 by flow cytometry, but there are no specific immunophenotypic features associated with other molecular abnormalities. Some rearrangements are detectable by conventional karyotype analysis, but others are cryptic [15]. Diagnosis of this condition generally requires gene expression analysis coupled with cytogenetic and molecular diagnostic testing [49].  

Approximately half of these cases have translocations involving CRLF2, while others have translocations involving tyrosine kinases (eg, JAK2, ABL1, ABL2, PDGFRB, NTRK3, TYK2, CSF1R) or activation of EPOR [6]. A high fraction of these tumors also has mutations in IKZF1 [50], a gene that encodes an important transcriptional regulator of lymphoid development. The incidence of specific rearrangements varies by age [15]. CRLF2 rearrangements are the most common alterations across all age groups [15]. ABL fusions are more frequent in children and JAK2 rearrangements have an increased incidence in young adults [15]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'BCR::ABL1-like B cell ALL'.)

This category of B cell ALL/LBL is associated with poor outcomes, and cases with CRLF2 translocations have especially poor prognosis [51-57].

iAMP21 — Amplification of a portion of chromosome 21 is typically detected by FISH probe for RUNX1 that reveals ≥5 copies of the gene (or ≥3 extra copies on a single abnormal chromosome 21) [58,59]. This abnormality is less common in adults. B cell ALL/LBL is increased 3000-fold in individuals with constitutional Robertsonian translocation rob(15;21)(q10;q10) due to chromothripsis; this mechanism may also contribute to sporadic cases of iAMP21 [60].

This entity accounts for approximately 2 percent of B cell ALL, and is usually found in older children, especially those who present with a low WBC count [1,6].

In most cases, iAMP21 is associated with other chromosomal changes. It is associated with poor prognosis in children, although more intensive therapy may overcome this adverse risk [58]. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Structural abnormalities'.)

Other genetic subtypes — Molecular and genetic evaluation of a cohort of nearly 2000 cases of childhood and adult B cell ALL/LBL identified additional distinct genetic subtypes that have yet to be incorporated into the WHO classification [61]. These include subtypes defined by structural rearrangements in the genes DUX4, NUTM1, MEF2D, ZNF384, and MYC, and other genetic aberrations involving PAX5 and IZKF1. The most common of these subtypes, defined diverse PAX5 alterations, constituted 7 percent of cases in this series and had features associated with high-risk disease in children. Additional studies are needed to evaluate these new genetic subtypes, which are likely to be incorporated into future WHO classifications.

PROGNOSIS — Prognosis in B cell ALL/LBL is associated with age, clinical features, and cytogenetic/genetic features (table 2). The role of minimal residual disease testing in assessing response to therapy and prognosis is discussed separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia" and "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Clinical features that are associated with unfavorable prognosis include:

Age (≤1 year or ≥10 years old)

Many infants have translocations involving the KMT2A (MLL) at 11q23, which is associated with a poor prognosis at any age [27].

Older children more often have hyperdiploidy and t(12;21), which confer a better prognosis [33].

Adult B cell ALL/LBL is more often associated with t(9;22) or poor risk t(v;11q23.3) abnormalities, and survival is poorer than in childhood cases [26,62].

Leukocyte count ≥50,000/microL

Race (Hispanic or Black) due to genomic variations and socioeconomic factors [53,63,64]

Male sex

Clinical features that are associated with outcomes in B cell ALL/LBL are discussed in more detail separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Clinical features'.)

The relationship between prognosis and cytogenetic abnormalities in ALL is discussed above and separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma" and "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Cytogenetics'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) (The Basics)")

Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY

Description – B cell acute lymphoblastic leukemia/lymphoma (B cell ALL/LBL) is a malignancy of immature B cells that is most common in children (three-quarters of cases are in children <6 years old), but there is a second peak of incidence in adults >60 years old. (See 'Epidemiology' above.)

Leukemia and lymphoma are overlapping clinical presentations of the same disease (ie, B cell ALL/LBL); diagnosis and classification do not distinguish between these entities.

Clinical features – Most patients have findings associated with anemia, neutropenia, and/or thrombocytopenia. Symptoms can include fatigue, infections, bleeding, bone pain, arthralgias, or constitutional symptoms. Hepatomegaly, splenomegaly, lymphadenopathy, and/or central nervous system findings may be present. (See 'Clinical features' above.)

Pathologic features – The white blood cell (WBC) count may be decreased, normal, or markedly elevated. Peripheral blood smear, bone marrow biopsy, and tissue biopsy demonstrate generally small to medium-sized lymphoblasts with uniform appearance and scant cytoplasm. (See 'Morphology' above.)

Evaluation – Includes complete blood count with differential count, examination of the blood smear, immunophenotype of blood or marrow, and bone marrow examination; lymph node biopsy may be included for some patients.

Diagnosis – B cell ALL/LBL is usually suspected in a child or adult with circulating lymphoblasts and/or painless lymphadenopathy; it may be suspected in the setting of unexplained cytopenias or associated symptoms, constitutional symptoms, bone pain, and/or organomegaly. (See 'Evaluation and diagnosis' above.)

Diagnosis requires demonstration of B lymphoblasts with the characteristic immunophenotype in blood, bone marrow, or other involved tissue (see 'Evaluation and diagnosis' above):

B cell antigens are expressed: CD19, cytoplasmic CD79a, and/or cytoplasmic CD22; although the individual markers are not specific for B cell ALL/LBL, their positivity in combination or with high intensity strongly supports the diagnosis.

T cell antigens are not expressed: T cell antigens (eg, CD3) are negative.

Myeloid antigens may be expressed: CD13 and/or CD33 may be expressed and do not exclude the diagnosis of B cell ALL/LBL; in contrast, myeloperoxidase (MPO) is considered myeloid lineage-defining, and its expression excludes the diagnosis of B cell ALL/LBL.

Classification – All cases of B cell ALL/LBL should be categorized according to the World Health Organization (WHO) classification, based on cytogenetic/genetic features. (See 'Classification of B cell ALL/LBL' above.)

Differential diagnosis – Includes other leukemias (eg, T cell ALL/LBL, Burkitt lymphoma, other acute leukemias, chronic myeloid leukemia) and lymphoproliferative disorders, as well as certain nonmalignant processes, including infectious and reactive/inflammatory processes, and hematogones (normal developing pre-B cells in infants and very young children). (See 'Differential diagnosis' above.)

Prognosis – Outcomes are associated with age, WBC count, race, male sex, and cytogenetic/genetic features (table 2). (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.

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